Alkanes in Minisci-Type Reaction under Photocatalytic Conditions with Hydrogen Evolution.

We report herein a protocol for the selective activation of C(sp3)-H bonds based on the interplay of two readily available organic catalysts and their successful implementation in cross-coupling azaarenes with alkanes. This Minisci-like reaction is promoted by visible light at room temperature and is free from chemical oxidants, metals, and chlorinated solvents. A wide range of substrates are compatible, including some bioactive molecules. Mechanistic studies support a dual catalytic cycle with H2 evolution.

Visible-light-mediated decarboxylative (E)-alkenylation of aliphatic carboxylic acids with aryl styryl sulfones under metal-free conditions.

The decarboxylative alkenylation of aliphatic carboxylic acids with aryl styryl sulfones is efficiently catalyzed by riboflavin tetraacetate under visible light irradiation at room temperature. This metal-free protocol is cost-efficient, environmentally friendly and provides the corresponding olefins with excellent (E)-diastereocontrol. The methodology can also be used to prepare internal alkynes regioselectively by using alkynyl sulfones as radical acceptors. The suitability as building blocks of the olefins obtained was demonstrated by performing an (E)- to (Z) photoisomerization, an iron-catalyzed allylic substitution of the phenoxy group derived from the 2-phenoxycarboxylic acid substrates, as well as syn-epoxidations, and diastereoselective intramolecular iodoarylations. Based on control experiments and DFT calculations, we proposed a reaction mechanism that accounts for the regio- and diastereo-selectivity observed.

Radical Arylation of Triphenyl Phosphite Catalyzed by Salicylic Acid: Mechanistic Investigations and Synthetic Applications.

A straightforward and scalable methodology to synthesize diphenyl arylphosphonates at 20 °C within 1-2 h is reported using inexpensive SA as the catalytic promoter of the reaction. Mechanistic investigations suggest that the reaction proceeds via radical-radical coupling, consistent with the so-called persistent radical effect. The reaction tolerated a wide range of functional groups and heteroaromatic moieties. The synthetic usefulness and the unique reactivity of the obtained phosphonates were demonstrated in different one-step transformations.

Decarboxylative Cyanation of Aliphatic Carboxylic Acids via Visible-Light Flavin Photocatalysis.

An operationally simple method is disclosed for the decarboxylative cyanation of aliphatic carboxylic acids at room temperature. Riboflavin tetraacetate, which is an inexpensive organic photocatalyst, promotes the oxidation of carboxylic acids upon visible-light activation. After decarboxylation, the generated radicals are trapped by TsCN, yielding the desired nitriles without any further additive, in a redox-neutral process. Importantly, this protocol can be adapted to flow conditions.

A photoredox-neutral Smiles rearrangement of 2-aryloxybenzoic acids.

We report on the use of visible light photoredox catalysis for the radical Smiles rearrangement of 2-aryloxybenzoic acids to obtain aryl salicylates. The method is free of noble metals and operationally simple and the reaction can be run under mild batch or flow conditions. Being a redox neutral process, no stoichiometric oxidants or reductants are needed.

A radical addition/cyclization of diverse ethers to 2-isocyanobiaryls under mildly basic aqueous conditions.

Mildly basic aqueous conditions facilitated the tert-butyl peroxybenzoate (TBPB) mediated dehydrogenative addition of a range of ethers, including acetals, to diverse substituted 2-isocyanobiaryls. Mechanistic studies suggest that this radical cascade is an example of base promoted homolytic aromatic substitution (BHAS).

Concise asymmetric syntheses of novel phenanthroquinolizidines.

The first preparation of enantioenriched phenanthroquinolizidines with a quaternary center at C14a was accomplished in seven steps from readily available starting materials. Key steps were an efficient dynamic kinetic allylation of a diastereomeric mixture of chiral tert-butylsulfinyl ketimines and the construction of a piperidine E ring by rhodium catalyzed hydroformylation. The Stevens rearrangement of the corresponding N-benzyl derivatives took place smoothly, allowing the installation of a benzyl moiety at C9 in a trans relationship with the methyl group. The cytoxicity of the prepared phenanthroquinolizidines was evaluated against different human cancer cell lines.

Photocatalytic Dehydrogenative Lactonization of 2-Arylbenzoic Acids.

A metal-free dehydrogenative lactonization of 2-arylbenzoic acids at room temperature was developed. This work illustrates the first application of visible-light photoredox catalysis in the preparation of benzo-3,4-coumarins, an important structural motif in bioactive molecules. The combination of photocatalyst [Acr(+)-Mes] with (NH4)2S2O8 as a terminal oxidant provides an economical and environmentally benign entry to different substituted benzocoumarins. Preliminary mechanistic studies suggest that this reaction most likely occurs through a homolytic aromatic substitution pathway.

Syntheses and cytotoxicity of (R)- and (S)-7-methoxycryptopleurine.

Two efficient protocols are described for the transformation of a key chiral homoallyllic sulfinamine intermediate in four steps into enantioenriched 7-methoxycryptopleurine. While one of the protocols relied on a rhodium catalyzed linear hydroformylation process, the alternative approach was based on a ring-closing metathesis from the corresponding N-allyl-sulfinamine. The cytotoxic evaluation of both enantiomers of the target compound demonstrated that the (R)-compound is much more potent than its antipode against the four cancer cell lines examined.

Short asymmetric synthesis of phenanthroindolizidines through chiral homoallylic sulfinamines.

An efficient stereocontrolled preparation of chiral phenanthroindolizidines is detailed. The synthesis relies on the stereoselective indium-mediated allylation of 2-(phenanthren-9-yl)acetaldehyde derivatives with chiral tert-butylsulfinamide. Chemoselective transformations from the corresponding homoallylic sulfinamine allow the synthesis of the phenanthroindolizidines in only three synthetic operations, without any detectable racemization. Following this procedure, the synthesis of natural (-)-tylophorine was successfully accomplished.

Natural tetraponerines: a general synthesis and antiproliferative activity.

A stereocontrolled general methodology to access all natural tetraponerines from (+)-T1 to (+)-T8 is detailed. Two consecutive indium-mediated aminoallylations with the appropriate enantiomer of chiral N-tert-butylsulfinamide and a thermodynamic control at the aminal stereocenter allow the formation of each natural tetraponerine with excellent stereoselectivity. The use of 4-bromobutanal in the first aminoallylation leads to the formation of 5-6-5 tetraponerines, while 5-bromopentanal is required to build the scaffold of 6-6-5 tetraponerines. A cross-metathesis reaction of the second aminoallylation product with cis-3-hexene is used to elongate the side chain up to 5 carbons so as to prepare the tetraponerines T5 to T8. The anticancer activity of these heavier tetraponerines against four different carcinoma human cell lines is examined, observing a promising cytotoxic activity of (+)-T7 against breast carcinoma cell line MCF-7.

Regio- and stereoselective aminopentadienylation of carbonyl compounds.

A simple and robust protocol is detailed for the preparation of enantioenriched α-substituted (1,4-pentadien-3-yl)amine derivatives. The methodology involves the addition of an in situ formed pentadienyl indium reagent to chiral tert-butylsulfinimines, previously formed in the same pot. The addition takes place with excellent γ-regio- and diastereoselectivity for a wide range of carbonyl compounds, including α-unsubstituted aldehydes and methyl alkyl ketones. The catalytic hydrogenation of the sulfinamines obtained provides a convenient access to chiral α-substituted (3-pentyl)amines. The hydroboration-oxidation of the α-(1,4-pentadien-3-yl)amine derivatives, followed by a cyclization under Mitsunobu conditions, takes place with an excellent diastereoselectivity governed by the chiral sulfinyl group.

A general protocol to afford enantioenriched linear homoprenylic amines.

The reaction of a readily obtained chiral branched homoprenylamonium salt with a range of aldehydes, including aliphatic substrates, affords the corresponding linear isomers in good yields and enantioselectivities.

Concise total synthesis and stereochemical analysis of tetraponerines T3 and T4.

An efficient stereocontrolled preparation of tetraponerines T3 and T4 is detailed. The sequence takes advantage of two consecutive stereoselective aminoallylations of appropriate aldehydes with chiral tert-butanesulfinamide and in situ generated allyl indium species. The absolute configuration of the carbon stereogenic center at the aminal moiety is thermodynamically controlled. This was ascertained on the basis of an exhaustive DFT configurational study of tetraponerines, which fulfils the lack of detailed structural information for these systems. It was found that the trans-transoid-configuration of the AB rings is the most stable geometry for T3 and T4. However, the C ring prefers a cis-configuration in T3 (ttc-T3) and a trans-fusion in T4 (ttt-T4). Regarding their dynamic behavior, low activation barriers were found by DFT calculations for the inversion of the nitrogen at the indolizidine framework, allowing rapid equilibration between the major configurations (ttc and ttt) in T3 and T4.

Straightforward access to enantioenriched 2-allylpiperidine: application to the synthesis of alkaloids.

An efficient stereocontrolled preparation of (2R,R(S))-2-allyl-(N-tert-butylsulfinyl)piperidine and its enantiomer is detailed. The sequence requires only two synthetic operations with one-column chromatography and is readily scaled up. The versatility of these chiral building blocks was exemplified by the total or formal synthesis of some natural and unnatural alkaloids.

Stereoselective α-aminoallylation of aldehydes with chiral tert-butanesulfinamides and allyl bromides.

The combination of an aldehyde, an allylic bromide, and tert-butanesulfinamide in the presence of indium metal and titanium tetraethoxide allows straightforward access to homoallylamine derivatives in high yields and stereoselectivities. Moreover, the synthetic utility of the enantioenriched homoallylamine derived from n-decanal was illustrated in a concise synthesis of (+)-isosolenopsin. In this context, similar homoallylamines has been recently used by other groups in the synthesis of naturally occurring alkaloids.

Visible-light photoredox catalysis: aza-Henry reactions via C-H functionalization.

We report the application of visible-light photoredox catalysis for the formation of C-C bonds between tertiary N-arylamines and nitroalkanes via an oxidative aza-Henry reaction. In the presence of 1 mol % Ir(ppy)(2)(dtbbpy)PF(6), efficient coupling of nitroalkanes with in situ-generated iminium ions provides the desired products in up to 96% yield. Mechanistic studies suggest that reductive quenching of the Ir(3+) excited state by the tertiary amine leads to the ammonium radical cation, with subsequent catalyst turnover (Ir(2+) --> Ir(3+)) likely effected by atmospheric oxygen.

Efficiency in chemistry: from hydrogen autotransfer to multicomponent catalysis.

A hydrogen autotransfer reaction has been applied to the α-alkylation of ketones, with primary alcohols as the electrophilic component, either under homogeneous (using a Ru complex as catalyst) or under heterogeneous (using Ni nanoparticles) conditions. This process is both very efficient (concerning atom economy) and ecologically friendly (water as the only by-product generated). On the other hand, three multicomponent reactions, namely, the Strecker reaction (without any catalyst), the aza-Sakurai process (catalyzed by ferrite), and the addition of in situ generated Zn enolates to chiral sulfinylimines (catalyzed by Cu), have proven to be very efficient in the generation of a diversity of polyfunctionalized molecules.