Alicia B. Peñéñory

Competitive Reaction Pathways for o-Anilide Aryl Radicals: 1,5- or 1,6-Hydrogen Transfer versus Nucleophilic Coupling Reactions. A Novel Rearrangement to Afford an Amidyl Radical

The photoinduced reactions of o-iodoanilides (o-IC6H4N(Me)COR, 4a-d) with sulfur nucleophiles such as thiourea anion (1, -SCNH(NH2)), thioacetate anion (2, MeCOS-), and sulfide anion (3, S(2-)) follow different reaction channels, giving the sulfides by a radical nucleophilic substitution or the dehalogenated products by hydrogen atom transfer pathways. After an initial photoinduced electron transfer (PET) from 1 to iodide 4, the o-amide aryl radicals 12 are generated. These aryl radicals 12 afford alternative reaction pathways depending on the structure of the alpha-carbonyl moiety: (a) 12b (R = Me) adds to 1 to render the methylthio-substituted compounds by quenching the thiolate anion intermediate with MeI after irradiation; (b) 12c (R = -CH2Ph) follows a 1,5-hydrogen transfer to give a stabilized alpha-carbonyl radical (17); and (c) 12d (R = t-Bu) affords 1,6-hydrogen transfer, followed by a 1,4-aryl migration to render an amidyl radical (20), which is reduced to the N-benzyl-N,2-dimethylpropanamide (10). Together with this last rearranged product, the ipso substitution derivative was also observed. Similar results were obtained in the PET reactions of 4d (R = t-Bu) with anions 2 and 3 under entrainment conditions with the enolate anion from cyclohexenone (5) or the tert-butoxide anion (6). From this novel rearrangement, and only under reductive conditions by PET reaction with anion 5, iodide 4d (R = t-Bu) affords quantitatively the propanamide 10. The energetic of the intramolecular rearrangements followed by radicals 12b-d were rationalized by B3LYP/6-31+G* calculations.

A novel reaction of N-phenylthiocaprolactam: The α-sulfenylation of ketones under mild conditions

Abstract N-phenylthiocaprolactam ( 2 ) reacts with the enolate anions of aliphatic, aromatic or cyclic ketone 1a-e , to give the corresponding α -phenylthioketones 3a-e . This reaction proceeds with high yields of monosulphenylation (80–97%) in DMSO under mild conditions (potassium ter -butoxide, 25°C, 10 min).

Efficient Cu-catalyzed base-free C-S coupling under conventional and microwave heating. A simple access to S-heterocycles and sulfides.

Summary S-aryl thioacetates can be prepared by reaction of inexpensive potassium thioacetate with both electron-rich and electron-poor aryl iodides under a base-free copper/ligand catalytic system. CuI as copper source affords S-aryl thioacetates in good to excellent yields, by using 1,10-phenanthroline as a ligand in toluene at 100 °C after 24 h. Under microwave irradiation the time was drastically reduced to 2 h. Both procedures are simple and involve a low-cost catalytic system. This methodology was also applied to the “one-pot” synthesis of target heterocycles, such as 3H-benzo[c][1,2]dithiol-3-one and 2-methylbenzothiazole, alkyl aryl sulfides, diaryl disulfides and asymmetric diaryl sulfides in good yields.

An expedient route to heterocycles through α-arylation of ketones and arylamides by microwave induced thermal SRN1 reactions

Microwave irradiation promotes a quick aromatic nucleophilic substitution by a thermally induced electron transfer process to form new C–C bonds by the coupling of aryl radicals and enolate nucleophiles. Diverse 2-aryl-1-phenylethanones can be prepared by the direct α-arylation of acetophenone with different haloarenes. The ketone enolate anion is generated by deprotonation with tBuOK in DMSO and the reaction is carried out in a closed microwave vessel at 70–100 °C for 10 min. This simple procedure also allows the synthesis of deoxybenzoin and indole heterocycle derivatives by inter- or intra-molecular ring closure reactions, with moderate to excellent substitution yields.

Photoremoval of protecting groups: mechanistic aspects of 1,3-dithiane conversion to a carbonyl group.

Photodeprotection of 1,3-dithianes in the presence of thiapyrylium was performed to return to the parent carbonyl compound, and the mechanism was studied by steady state photolysis, laser flash photolysis, and theoretical calculations. Electron transfer from dithianes to triplet sensitizers is extremely fast, and the decay of dithiane radical cations was not affected by the presence of water or oxygen as the consequence of a favorable unimolecular fragmentation pathway. Similar behaviors were observed for dithianes bearing electron-releasing or electron-withdrawing substituents on the aryl moiety, evidenced by C-S bond cleavage to form a distonic radical cation species. The lack of reaction under nitrogen atmosphere, requirement of oxygen for good conversion yields, inhibition of the photodeprotection process by the presence of p-benzoquinone, and absence of a labeled carbonyl final product when the reaction is performed in the presence of H2(18)O all suggest that the superoxide anion drives the deprotection reaction. Density functional theory computational studies on the reactions with water, molecular oxygen, and the superoxide radical anion support the experimental findings.

Breaking bonds with electrons: stepwise and concerted reductive cleavage of C–S, C–Se and Se–CN bonds in phenacylthiocyanates and phenacylselenocyanates

The mechanistic aspects of the electrochemical reduction of phenacylthio- and selenocyanates have been studied. With phenacylthiocyanates (1), a change in the reductive cleavage mechanism is observed as a function of the substituent on the phenyl ring. While a stepwise mechanism involving the intermediacy of a radical anion is followed for substrates bearing a strong electron withdrawing group, such as cyano and nitro substituent (1d, 1e), and a concerted mechanism is favoured for compounds bearing an electron-donating or no substituent on the phenyl ring (1a–c). A regioselective bond cleavage leads to the fragmentation of the CH2–S bond with all compounds 1a–e, further yielding the corresponding 1,4-diketone (3) as products. Contrastingly, with phenacylselenocyanates (2), two different reductive cleavages occur involving the breaking of both the CH2–Se and Se–CN bonds. Several products are obtained, all coming from nucleophilic attack at the α (phenacyl) carbon or the selenium atom.

Microwave role in the thermally induced SRN1 reaction for α-arylation of ketones

The coupling between iodobenzene and the enolate anion of acetophenone is accelerated by microwave irradiation. This increase in reaction rate is only ascribed to thermal effects. The coupling reaction gave the corresponding substitution product 1,2-di-phenylethanone in a 50% yield when microwave irradiation was applied between 15–60 s according to the intensity of the pulse. Moreover, this reaction is effective in a temperature window of 70–120 °C. The presence of ionic and dipolar species is not involved in the initiation process as molecular radiators. The excess of tBuOK in the reaction medium may also act as an electron donor helping to generate radicals when the solution temperature increases to 70 °C.

Mechanistic Insight into the Cu-Catalyzed C–S Cross-Coupling of Thioacetate with Aryl Halides: A Joint Experimental–Computational Study

The mechanism of the Ullmann-type reaction between potassium thioacetate (KSAc) and iodobenzene (PhI) catalyzed by CuI associated with 1,10-phenanthroline (phen) as a ligand was explored experimentally and computationally. The study on C-S bond formation was investigated by UV-visible spectrophotometry, cyclic voltammetry, mass spectrometry, and products assessment from radical probes. The results indicate that under experimental conditions the catalytically active species is [Cu(phen)(SAc)] regardless of the copper source. An examination of the aryl halide activation mechanism using radical probes was undertaken. No evidence of the presence of radical species was found during the reaction process, which is consistent with an oxidative addition cross-coupling pathway. The different reaction pathways leading to the experimentally observed reaction products were studied by DFT calculation. The oxidative addition-reductive elimination mechanism via an unstable CuIII intermediate is energetically more feasible than other possible mechanisms such as single electron transfer, halogen atom transfer, and σ-bond methatesis.

Anions involved in the initiation of the thermally induced SRN1 reaction for α-arylation of ketones

The SRN1 reaction between acetophenone enolate and PhI is thermally induced and accelerated by microwave irradiation to give the corresponding substitution product 1,2-diphenylethanone in a 50% yield in DMSO at 70 °C. Regarding the mechanism of initiation, in this reaction, acetophenone enolate, tert-butoxyde anion and dimsyl anion (the ionic form of the solvent) could promote the initial electron transfer to start the radical reaction. Comparative studies on the PhI dehalogenation promoted by the different anions were conducted in DMSO under microwave irradiation and by quantum calculations. The dimsyl anion shows a higher iodide generation even at lower concentrations than acetophenone enolate and tBuO−. Likewise, DFT calculation by B3PW91, M062X and PBE0 shows the dymsyl anion to be the best electron donor. While the three anions can initiate the radical reaction, the reactivity order found locates the dimsyl anion in first place, followed by the enolate of acetophenone and then the alkoxide. The results reported herein allow a greater understanding of the initiation process with tert-butoxide solutions in DMSO.

Versatile one-pot synthesis of benzo-fused thiacycles by copper catalysis

A novel, one-pot synthesis of structurally diverse benzo-fused thiacycles via a Cu-catalysed intermolecular C–S coupling/cyclisation tandem process, employing the same catalytic system, has been developed. Thus, 3,4-dihydro-2H-benzo[e][1,3]thiazines and 4H-benzo[e][1,3]thiazines were selectively obtained by this one-pot tandem process from (2-iodophenyl)methanamine and aldehydes or 1-(azidomethyl)-2-iodobenzene, respectively. These reactions proceeded in toluene at 100 °C with potassium thioacetate, thiobenzoate or ethyl xanthogenate in moderate to good isolated yields. The first one avoids the imine isolation step. A similar approach to benzo[b]thiophene derivatives from 2-(2-iodophenyl)acetonitrile was also developed.