Intramolecular Radical Substitution Research Articles

A Radical Approach to Making Unnatural Amino Acids: Conversion of C-S Bonds in Cysteine Derivatives into C-C Bonds.

Here we report a general approach to make unnatural amino acids from readily available cysteine derivatives. This method capitalizes on an intramolecular radical substitution process that generates alkyl radicals through C-S cleavage. The resulting alkyl radicals partook in diverse C-C bond forming events. These reactions proceed under mild, photocatalytic conditions at room temperature, and can be performed open to air. The utility of these transformations is further demonstrated in the straightforward synthesis of various unnatural amino acids and peptides that are difficult to access previously.

A Radical Approach to Making Unnatural Amino Acids: Conversion of C−S Bonds in Cysteine Derivatives into C−C Bonds

AbstractHere we report a general approach to make unnatural amino acids from readily available cysteine derivatives. This method capitalizes on an intramolecular radical substitution process that generates alkyl radicals through C−S cleavage. The resulting alkyl radicals partook in diverse C−C bond forming events. These reactions proceed under mild, photocatalytic conditions at room temperature, and can be performed open to air. The utility of these transformations is further demonstrated in the straightforward synthesis of various unnatural amino acids and peptides that are difficult to access previously.

Generation of Glycosyl Radicals from Glycosyl Sulfoxides and Its Use in the Synthesis of C-linked Glycoconjugates.

We here report glycosyl sulfoxides appended with an aryl iodide moiety as readily available, air and moisture stable precursors to glycosyl radicals. These glycosyl sulfoxides could be converted to glycosyl radicals by way of a rapid and efficient intramolecular radical substitution event. The use of this type of precursors enabled the synthesis of various complex C-linked glycoconjugates under mild conditions. This reaction could be performed in aqueous media and is amenable to the synthesis of glycopeptidomimetics and carbohydrate-DNA conjugates.

Generation of Glycosyl Radicals from Glycosyl Sulfoxides and Its Use in the Synthesis of C‐linked Glycoconjugates

AbstractWe here report glycosyl sulfoxides appended with an aryl iodide moiety as readily available, air and moisture stable precursors to glycosyl radicals. These glycosyl sulfoxides could be converted to glycosyl radicals by way of a rapid and efficient intramolecular radical substitution event. The use of this type of precursors enabled the synthesis of various complex C‐linked glycoconjugates under mild conditions. This reaction could be performed in aqueous media and is amenable to the synthesis of glycopeptidomimetics and carbohydrate‐DNA conjugates.

Substituted 3-phenylpropenoates and related analogs: electron ionization mass spectral fragmentation and density functional theory calculations

Analysis of ethyl 3-(2-chlorophenyl)propenoate by electron ionization mass spectrometry showed the distinct loss of an ortho chlorine. To characterize the structural requisites for the observed mass fragmentation, a series of 30 halogen-substituted 3-phenylpropenoate-related structures were examined. All ester-containing alkene derivatives exhibited loss of the distinctive chlorine from the 2-position of the phenyl ring. Analogous derivatives with the halogen (chlorine or bromine) in the para position did not evidence selective halogen loss. Results demonstrated that substituted 3-phenylpropenoates and their analogs fragment via the formation of a previously reported benzopyrylium intermediate. To understand the correlation between the intramolecular radical substitution and the abundance and selectivity of the chlorine (or other halogen) displacement, density functional theory calculations were performed to determine the charge on the principal cation involved in the chlorine loss (in the ortho, meta, and para positions), the charge for the neutral radical (noncation), the excess alpha-electron density on the relevant atom and the energy to form the cation from the neutral atom (ionization energy). Results showed that the selectivity and extent of halogen displacement correlated highly to the electrophilicity of the radical cation as well as the neutral radical. These data further support the proposed fragmentation mechanism involving intramolecular radical elimination.

Preparation of fluorinated phenoxathiin dioxide monoamine oxidase‐A inhibitors: Intramolecular radical substitution at sulfur versus the mauthner synthesis

AbstractFive unique fluorinated analogs, 8a‐c and 15a,b, of the monoamine oxidase‐A inhibitor 3‐iso‐propoxyphenoxathiin 10,10‐dioxide (II) were prepared via oxidation of the corresponding phenoxathiins 7 and 14. 3‐Fluoro‐7‐isopropoxy‐ 7a, 2‐fluoro‐3‐isopropoxy‐ 7b, and 2,7‐difluoro‐3‐isopropoxyphenoxathiin (7c) were prepared by a modification of the Mauthner synthesis which involved cyclization of the corresponding 2‐hydroxy‐4‐isopropoxythiophenols 4 with the appropriate 2‐halonitrobenzenes 5 in the presence of potassium tert‐butoxide. Preparation of 2,8‐difluoro‐3‐isopropoxyphenoxathiin (14b) from 4b and 2,4‐difluoronitrobenzene (5c) employing similar methods failed, leading instead to a novel macrocycle 9. Attempts to obtain 2‐fluoro‐7‐isopropoxyphenoxathün (14a) and the 2,8‐difluoro analog 14b via trifluoroacetic acid deprotection of intermediate thio‐protected 2‐nitrophenyl 2‐thiophenyl ethers 11a and c followed by cyclization of the resulting thiols were also unsuccessful. Deprotection of 11a with trifluoroacetic acid produced only complex product mixtures, while similar deprotection of 11c and treatment of the resulting crude product with potassium tert‐butoxide in refluxing dimethylformamide produced the 2,7‐difluorophenoxathiin analog 7c, a result consistent with a Smiles rearrangement of the intermediate thiol 12 prior to ring closure. The phenoxathiins 14 were ultimately prepared by a modification of a relatively unexploited phenoxathiin synthesis involving the intramolecular radical substitution at sulfur of 2‐aminophenyl 2‐thiophenyl ethers 13 containing para‐methoxybenzyl and methoxymethylthio‐protecting groups.

Intramolecular radical substitution reactions: a novel approach to fused [1,2-a] indoles

A new approach to fused [1,2-a]indoles 25, 26 and 27 is described; the synthesis is based on a novel intramolecular radical cyclization reaction involving ipso-substitution using sulfone, sulfide and sulfoxide substituted indoles. Some more general aspects of scope and limitation of the process are presented including vinyl and aryl radical cyclizations of 29 and 30; investigations using substituted indoline and aniline derivatives 35 and 37 are also discussed.

Leveling of reactivity for intramolecular radical substitution reactions in viscous media

A leveling of the reactivity was found for intramolecular radical reactions in substituted 2-oxyphenoxyls in viscous media. A comparison of rate constants in toluene, hexane, pentane, and vaseline oil shows that fast reactions are decelerated more rapidly than slow reactions.

Cyclizations. Part 1. Electrochemical and photochemical reactions of 1-(4-fluorophenyl)-5-(2-halogenophenyl)tetrazoles

Electrochemical reduction of the title compounds, where the halogen substituent is Cl, Br or I, leads to cleavage of the carbon–halogen bond to leave a phenyl radical. Competition then follows between intramolecular radical substitution giving 7-fluorotetrazolo[1,5-f]phenanthridine and further reduction of the radical, then protonation, giving 1-(4-fluorophenyl)-5-phenyltetrazole. Substitution predominates but reduction and protonation becomes a more competing reaction when the halogen is Br or I. Photochemical reaction of the title compounds shows competition between carbon–halogen bond cleavage to give 7-fluorotetrazolo[1,5-f]phenanthridine and loss of nitrogen followed by cyclization to give 2-halogenophenyl-5-fluorobenzimidazole. Carbon–halogen bond cleavage predominates and becomes the only reaction when the halogen is I. The fluorine substituent allows the determination of product yields by 19F NMR spectroscopy.

Intramolecular radical substitution on the sulfur of thioester, sulfide, sulfoxide, and sulfone

Alkyl radicals having the sulfur functions such as thioester, sulfide, and sulfoxide at the γ-position gave five membered cyclic thiolactone, sulfide and sulfoxide, while sulfone did not react with the alkyl radical. The product expectad from the sulfuranyl radical intermediate, which can pseudo-rotate, was not obtained.

A Radical Substitution on Sulfur of Thioester Group. Formation of β- and γ-Thiolactone

Abstract Alkyl radicals having (t-butylthio)carbonyl group on β- or γ-position gave β- or γ-thiolactones whereas the homologous radical did not give δ-thiolactone. These reactions involve intramolecular radical substitution on the sulfur atom of thioester group. Ethylthioesters have much less reactivity to the same substitution.

Electrochemical reactions. Part 23. Intramolecular radical substitution during the reduction of 2-halogeno-N-methyl-N-naphthylbenzamides

Phenyl radical intermediates formed by the reductive cleavage of the carbon-halogen bond in 2-halogeno-N-methyl-N-(1-naphthyl)benzamides undergo intramolecular substitution to give N-methyl-2-(1-naphthyl)benzamide, and no N-methylbenzo[c]phenanthridone is formed. Reduction of 2-halogeno-N-methyl-N-(2-naphthyl)benzamides gives N-methyl-2-(2-naphthyl)benzamide, N-methylbenzo[a]phenanthridone, and N-methylbenzo[b]phenanthridone. These results complete our comparison of this electrochemical reaction with related radical Pschorr cyclisations. Further reduction of these initial reaction products occurs so that only qualitative conclusions can be drawn from the product yields.

Tautomerism in silicon-containing free radicals

Silicon-containing free radicals with 3,6-di-t-butylpyrocatechinic ligands have been investigated by ESR method. Intramolecular migrations of free valence and bond was found for these systems. It was considered in terms of intramolecular radical substitution.

Electrochemical reactions. Part 19. Intermolecular radical substitution during the reduction of 2-halogeno-N-methylbenzanilides

The reduction of 2-halogeno-N-methylbenzanilides gives N-methyl-N-phenylcarbamoylphenyl radicals, which (i) react by substitution to yield phenanthridones and biphenyl-2-carboxamides or (ii) are reduced further to the N-methylbenzanilide. Occurrence of the substitution process confirms the presence of phenyl radical intermediates. The maximum yield of intramolecular substitution products is limited by the proportion of syn-amide rotamer present at equilibrium. When the halogen is chlorine, intramolecular trapping of the resulting phenyl radical is an efficient process and only the anti-amide rotamer forms the N-methylbenzanilide. When the halogen is bromine or iodine a significant proportion of the phenyl radical derived from the syn-amide rotamer is also converted by further reduction and protonation into the N-methylbenzanilide. Intramolecular radical substitution leads to both phenanthridones and biphenyl-2-carboxamides when the aniline component of the N-methylbenzanilide does not carry an ortho-substituent. Only the biphenyl-2-carboxamide is formed when an ortho-substituent is present on the aniline component. These results are compared with the results from related radical reactions.