Smiles-type Rearrangement Research Articles

Facile Smiles‐type rearrangement in radical cations of N‐acyl arylsulfonamides and analogs

N-Alkylation of sulfonylbenzamides was reported recently to cause a dramatic and surprising change in electron ionization mass spectrometry (EIMS), leading to a closed-shell base peak. Only an incomplete, speculative mechanism was available at that time. The fragmentation mechanism is determined in the present work and set in the context of related compounds. Candidate reaction mechanisms were evaluated theoretically using modest density-functional calculations. The fragmentation mechanism with the lowest barriers was identified and one of its implications tested successfully by experimental (18) O-isotopic substitution. The amide oxygen atom attacks the arylsulfonyl group at the ipso position (Smiles-type rearrangement), displacing a molecule of SO2 . The resulting carboximidate radical cation has a weak C-O bond that breaks easily. The incipient aryloxyl radical abstracts a proton from the amide nitrogen to form the dominant product ion, but if the molecule is N-alkylated this cannot occur. Instead, the neutral aryloxyl radical is lost and a closed-shell, N-alkyl nitrilium ion is the major product. The Smiles-type ion fragmentation mechanism is facile for the title compounds, despite the necessity for carbonyl oxygen to serve as a nucleophile. This rearrangement probably occurs in many of the mass spectra reported for structurally similar compounds, in which the nucleophile may be a thione, arylthio, imine, methylene, or methine moiety.

Transformation of Sulfamethazine by Manganese Oxide in Aqueous Solution

The transformation of the sulfonamide antimicrobial sulfamethazine (SMZ) by a synthetic analogue of the birnessite-family mineral vernadite (δ-MnO(2)) was studied. The observed pseudo-first-order reaction constants (k(obs)) decreased as the pH increased from 4.0 to 5.6, consistent with the decline in δ-MnO(2) reduction potential with increasing pH. Molecular oxygen accelerated SMZ transformation by δ-MnO(2) and influenced the transformation product distribution. Increases in the Na(+) concentration produced declines in k(obs). Transformation products identified by tandem mass spectrometry and the use of (13)C-labeled SMZ included an azo dimer self-coupling product and SO(2) extrusion products. Product analysis and density functional theory calculations are consistent with surface precursor complex formation followed by single-electron transfer from SMZ to δ-MnO(2) to produce SMZ radical species. Sulfamethazine radicals undergo further transformation by at least two pathways: radical-radical self-coupling or a Smiles-type rearrangement with O addition and then extrusion of SO(3). Experiments conducted in H(2)(18)O or in the presence of (18)O(2)(aq) demonstrated that oxygen both from the lattice of as-synthesized δ-MnO(2) and initially present as dissolved oxygen reacted with SMZ. The study results suggest that the oxic state and pH of soil and sediment environments can be expected to influence manganese oxide-mediated transformation of sulfonamide antimicrobials.

Synthesis of fluorinated fused benzofurans and benzothiophenes: Smiles-type rearrangement and cyclisation of perfluoro(het)aryl ethers and sulfides

Lithium-bromine exchange in 2-bromophenyl perfluoroaryl ethers or sulfides affords fused fluorinated benzofurans or benzothiophenes respectively by S(N)Ar substitution of the adjacent fluorine in the perfluoroaryl substituent. The structures of the new compounds were confirmed by NMR spectroscopy and single crystal X-ray diffraction analysis. In the case of 2-bromophenyl tetrafluoropyrid-4-yl ether, lithiation promoted a Smiles-type rearrangement which led to formation of 4-(2-hydroxyphenyl)tetrafluoropyridine, for which the structure was confirmed by X-ray crystallography.

Polycyclic N-heterocyclic compounds. Part 61: A novel Truce–Smiles type rearrangement reaction of 4-(2-cyanovinyloxy)butanenitriles to give cycloalkeno[1,2- d]furo[2,3- b]pyridines

The cycloalkeno[1,2- d]furo[2,3- b]pyridine skeleton was conveniently synthesized from fused 4-(2-cyanovinyloxy)butanenitriles in one step through sequential intramolecular Michael addition, β-elimination and intramolecular nucleophilic addition. This sequence thus consists of a novel Truce–Smiles type rearrangement followed by cyclization. The 5-amino derivatives were transformed further to lactams in good yields.

Synthesis and Mass Spectral Studies of Some (E)- and (Z)-1-Alkylthio - and 1-Alkylsulphonyl-2-P-Tolylsulphonylstilbenes

A number of (E)- and (Z)-1-alkylthio-2-p-tolylsulphonylstilbenes (3a–i and 5a–i) were synthesized by the nucleophilic displacement of halogens with sodium salts of various alkanethiols on (E)-1-chloro-2-p-tolylsulphonylstilbene (1) and (Z)-1-bromo-2-p-tolylsulphonylstilbene (2) respectively. Oxidation of these (E) - and (Z)-1-alkylthio-2-p-tolylsulphonyl gave the corresponding (E)- and (Z)-1-alkylsulphonyl-2-p-tolylsulphonylstilbenes (4a–i and 6a–i) respectively. Mass spectral data of all the synthesized compounds were examined. Smiles-type rearrangement observed in (E)-and (Z)- sulphide-sulphones (3a–i and 5a–i) was absent in (E)- and (Z)-disulphones (4a–i and 6a–i). Loss of sulphur dioxide and sulphonyl-sulphinate rearrangement with vinyl migration was noticed in all the synthesized compounds. McLafferty-type rearrangement was observed only in (E)- sulphide-sulphones and (E)- disulphones but not in the corresponding (Z)-isomers.

Synthesis of 2,4-Disubstituted Piperidines via Radical Cyclization: Unexpected Enhancement in Diastereoselectivity with Tris(trimethylsilyl)silane

A novel approach to 2,4-disubstituted piperidines is reported, involving the radical cyclization of 7-substituted-6-aza-8-bromooct-2-enoates. Cyclization with tributyltin hydride affords the trans piperidines with trans/cis diastereomeric ratios ranging typically from 3:1 to 6:1. Cyclization with tris(trimethylsilyl)silane affords the same products with diastereomeric ratios of up to 99:1 in certain cases. The enhancement in diastereoselectivity results from the selective rearrangement of the minor stereoisomer through a cascade process involving radical cyclization to the piperidine radical, 1,5-radical translocation, and attack of the translocated radical onto the sulfonamide with extrusion of SO2 in a Smiles-type rearrangement. Slower trapping of the piperidine radical by tris(trimethylsilyl)silane compared to tributyltin hydride accounts for the occurrence of the rearrangement cascade in the former case.

Smiles-type free radical rearrangement of aromatic sulfonates and sulfonamides: syntheses of arylethanols and arylethylamines.

Smiles-type free radical rearrangements of arenesulfonates and arenesulfonamides are exploited for synthetic purposes. 4-Substituted benzenesulfonates cause Smiles-type rearrangement only when substituted by an electron withdrawing group. Therefore, ipso-attack by an alkyl radical on arenesulfonates takes place in an electrophilic manner. Arenesulfonamides rearrange only when the amide nitrogen is substituted by an alkoxycarbonyl group, due to the electron withdrawing nature of this group. Sulfonates and the N-ethoxycarbonylsulfonamide derivatives of naphthalene, quinoline, and thiophene cause more rearrangement and show synthetic utility. Aromatic amino acid analogues were synthesized by Smiles-type rearrangement with moderate yields. The radical Smiles-type rearrangement of sulfonate and sulfonamide derivatives can be a useful synthetic route when we understand the electronic character of these reactions.

Synthesis of 5-alkyl-4-amino-2-(trifluoromethyl)pyridines and their transformation into trifluoromethylated 1H-pyrazolo[4,3-c]pyridines

5-Alkyl-4-amino-2-(trifluoromethyl)pyridines were prepared in good yields starting from the corresponding pyridinols either using condensation with tosyl isocyanate or by alkylation with 2-chloroacetamide and subsequent Smiles type rearrangement. The cyclisation of diazonium salts, generated from 5-alkyl-4-amino-2-(trifluoromethyl)pyridines, afforded trifluoromethylated 1H-pyrazolo[4,3-c]pyridines.

Unexpected Truce–Smiles type rearrangement of 2-(2′-pyridyloxy) phenylacetic esters: synthesis of 3-pyridyl-2-benzofuranones

Enolization of 2-(2′-pyridyloxy)phenylacetic acid esters with either potassium or sodium hydride induced a Truce–Smiles rearrangement, producing pyridine substituted 2-benzofuranones. Rearrangement of a 2-(4-nitrophenoxy)phenylacetate and a 2-(2′-pyrimidyloxy)phenylacetate produced similar results.

Self-assembly in the metallation of bis(aminoaryl) ethers

The dilithiation of 2,2′-bis(2-methoxyethylamino)diphenyl ether ( 4) and 2,2′-bis( N, N-dimethylethylenediamino)diphenyl ether ( 7) in the absence of any Lewis base donor resulted in the formation of dimeric complexes 8 and 9, respectively, containing the unprecedented Li 4O 2N 4 “adamantanoid” metal core as a consequence of the self-recognition and self-assembly involving the two metallated subunits. In contrast, on monometallation using particular conditions, e.g. sodium hydride in the presence of Lewis base donor, the same ligands undergo a Smiles-type rearrangement, providing the first example of such a reaction involving an amine and a deactivated aromatic system. The conditions needed to promote this rearrangement have been investigated.

Synthesis of thieno[2,3-h][1,6]naphthyridine from 2-(3-cyanopropylthio)pyridine-3-carbonitrile: formation of a novel ring system

An efficient methodology for the synthesis of novel ring system, thieno[2,3-h][1,6]naphthyridine, via a Smiles type rearrangement reaction and cyclization is described, its structure is confirmed by an X-ray structure analysis.

SYNTHESIS AND MASS SPECTRAL REARRANGEMENTS OF SOME NEW MIXED VINYL SULPHIDE-SULPHONES AND DISULPHONES

Abstract Stererospecifically prepared (E)-1-chloro-2-p-chlorophenylsulphonylstilbene (1) and (Z)-1-bromo-2-p-chlorophenylsulphonylstilbene (6) on reaction with sodium alkyl thiolates in abs. ethanol underwent nucleophilic displacement of halogens leading to the formation of (E)- and (Z)-1-alkylsulphenyl-2-p-chlorophenylsulphonylstilbenes (2 and 7). The sulphide-sulphones 2 and 7 on oxidation afforded the corresponding disulphones (3 and 8). Mass spectra of (E)- and (Z)-isomers of 1-butylsulphenyl-2-p-chlorophenylsulphonylstilbenes (2c and 7c) and their corresponding disulphones 3c and 8c are examined at 70 eV. Smiles type rearrangement is noticed only in 2c and 7c but not in 3c and 8c. McLafferty type rearrangement involving migration of hydrogen from aryl and/or alkyl groups to ethylenic carbon is observed both in sulphide-sulphones and in disulphones. Sulphonyl-sulphinate rearrangement with vinyl migration as the predominant pathway is a noted feature in both sulphide-sulphones and disulphones.

Chain length dependent reactivity of 2-(ω-hydroxyalkyl)-4-(ω-hydroxyalkylamino)phthalazin-1(2h)-ones in azeotropic hydrobromic acid

In boiling 48% HBr conversions of title compounds ( 5a - f ) resulted in 2-(ω)-bromoalkyl)-4-(2-hydroxyethylamino)-phthalazinones 8a , c , angular tricycles 7a , c - f and the 14a tricyclic dione, respectively, depending on the lengths of the side chains and the reaction time applied. The large difference between the reactivities of 4-(2-hydroxyethylamino)- and 4-(3-hydroxypropylamino) homologues in the exchange OH → Br was interpreted on the basis of the relative OH-basicities in the N 3-protonated molecules. The proposed mechanism for the conversion to 14a involving a Smiles-type rearrangement was supported by additional experiments with 4-amino-2-(ω-hydroxyalkyl)-phthalazinones 15a , b .

SYNTHESES AND MASS SPECTRAL REARRANGEMENTS OF UNSATURATED BIS-SULPHIDES AND BIS-SULPHONES

Abstract The synthesis of (E)- and (Z)-1.2-bis(p-fluorophenylsulphenyl)stilbenes (2a and 2b) and 1,2-bis(p-fluorophenylsulphonyl)stilbenes (3a and 3b) was carried out and their configurations were consistent with their stereospecific synthesis. The isomeric 1,1-bis(p-fluorophenylsulphenyl)- and 1,1-bis(p-fluorophenylsulphonyl)-2,2-bis(phenyl)ethylenes (8 and 9) were also synthesised and configurations were established by degradative oxidation. Mass spectral rearrangements of all these compounds were examined. Mass spectra of 1,1-bis-sulphide and 1,1-bis-sulphone bears close relationship with those of (E)- and (Z)-isomeric counterparts. Smiles-type rearrangement observed in 1,2-bis-sulphides was absent in 1,2-bis-sulphones. McLafferty-type rearrangement involving hydrogen migration, from aryl group was noticed in both bis-sulphides and bis-sulphones. Vinyl migration to the sulphone oxygen predominates over aryl migration in three isomeric bis-sulphones.

Molecular rearrangement of 5-(a-hydroxy-alkanoylamino)-2,4,6-triiodo-isophthalic acid amides.

Iomeprol, a new nonionic contrast agent, undergoes in alkaline solution a Smiles-type intramolecular rearrangement to give 5-methylaminocarbonylmethoxy-2,4,6-triiodoisophthalic acid-bis-(2,3-dihydroxypropylamide). The rearranged product was isolated and its structure confirmed by spectra and by synthesis. The reaction is reversible and could be extended to some structurally related compounds.

Pyridazine-4,5-dicarboxylic anhydride: versatile synthon for the preparation of 1,3,7,8-tetra-azaspiro[4.5]decane derivatives with nitrogen 1,3-binucleophiles

The title compound (1) reacted smoothly with 1,2,3-triphenyl- and 1,3-diphenyl-guanidine, with N,N′-diphenyl- and N-phenyl-thiourea, and with benzamidine to give in very good yields the 1,3,7,8-tetra-azaspiro[4.5]decane derivatives (2), (4), (6), (9), and (11), respectively, through a Smiles-type rearrangement. The reaction of compound (1) with 1,3-diphenylguanidine showed a different regiospecificity from that observed for the spiro-cyclization of dimethyl pyridazine-4,5-dicarboxylate (15) into methyl 4-oxo-1-phenyl-2-phenylimino-1,3,7,8-tetra-azaspiro[4.5]deca-6,9-diene-10-car-boxylate (19), carried out with the same reagent in the presence of sodium hydride. The structures of the new heterospiro compounds were determined on the basis of chemical and spectroscopic evidence.

Kinetic Studies on the N,N-Type Smiles Rearrangement

Abstract The Smiles rearrangement reaction of Dl-2-aminododecanoic acid N-methyl-p-nitroanilide to Dl-2-(p-nitrophenyl)aminododecanoic acid N-methylamide has been investigated in aqueous alkaline media containing 0–50% (v/v) acetonitrile or ethanol at 25 °C. It was found from the pH-rate profile that the reactive species is the free base form of the substrate. Acetonitrile content in the medium appreciably affected the rate with a maximum at ca. 20% in the acetonitrile content. The cationic CTAB micelles accelerated the rate 4.4-fold at pH 10, while the anionic SDS micelles suppressed the reaction almost completely. These effects of solvent and micelles were qualitatively correlated with the transition state of the reaction. A plausible mechanism for this reaction is the Smiles type rearrangement in which a spiro σ-complex is involved. The activation parameters obtained and suppression of the reaction rate by Cu(II) ion are in line with the proposed reaction mechanism.

The mass spectral rearrangements of aryl propenyl sulfones. An electron impact induced smiles type rearrangement

AbstractThe mass spectral behavior of trans‐1‐arylsulfonyl‐2‐arylsulfenyl‐propenes, trans‐1‐arylsulfonyl‐2‐arylsulfinyl‐propenes and trans‐1, 2‐(arylsulfonyl)‐propenes was examined. A Smiles type rearrangement was present in the sulfonyl‐sulfides, but was completely absent in the trans‐1‐arylsulfonyl‐2‐arylsulfinyl‐propenes and trans‐1, 2‐(arylsulfonyl)‐propenes. Vinyl migration to the sulfone oxygen predominates over aryl migration in all of the compounds studied. The mass spectra of the cis and trans isomers of 1‐p‐tolylsulfenyl‐2‐p′‐tolysulfonyl‐propene and 1, 2‐(p‐tolylsulfonyl)‐propene are also described.

Polyhalogeno-aromatic compounds. Part XXVIII. Derivatives of polyhalogenopyridine-4-thiols

The tetrachloropyridine-4-sulphonamides (1)–(3) were prepared from tetrachloropyridine-4-sulphonyl chloride and allylamine, n-butylamine, or ethanolamine at low temperatures. Tetrachloropyridine-4-(N-2-hydroxyethyl)sulphonamide (3) can undergo a double Smiles-type rearrangement (Scheme 1) on treatment with base at room temperature to give N-(tetrachloro-4-pyridyl)ethanolamine (4). Some reactions of 3,5-dichloro-2,6-difluoro-(7) and 2,3,5-trichloro-6-fluoro-pyridine-4-thiol (8) are reported.