Photoredox-Catalyzed Synthesis of Alkylaryldiazenes: Formal Deformylative C-N Bond Formation with Alkyl Radicals.

Diazenes are valuable compounds that have found broad applicability because of their optical and biological properties. We report the synthesis of alkylaryldiazenes via formal, photoredox-catalyzed, deformylative C-N bond formation. The procedure employs dihydropyridines for the generation of alkyl radicals, which are then trapped by diazonium salts and reduced to the corresponding diazenes. Control experiments were performed to confirm the involvement of radicals in the mechanism. The reaction can be carried out at room temperature and employs readily available reagents; the mild conditions allowed the use of highly functionalized substrates. There was no observed tautomerization of the diazenes to the corresponding arylhydrazones.

Enantioselective Synthesis of Phthalides and Isochromanones via Heck-Matsuda Arylation of Dihydrofurans.

In this communication, the enantioselective synthesis of phthalides and isochromanones is described through a new palladium-catalyzed Heck-Matsuda arylation/NaBH4 -reduction/lactonization sequence of 2,3- and 2,5-dihydrofurans in good overall yields and excellent enantioselectivities (up to 98:2 er). This expeditious synthesis of chiral Heck lactol intermediates allowed the diversification of the strategy to obtain medicinally relevant chiral lactones, amines, and olefins. The natural product 3-butylphthalide was obtained in three steps with an overall yield of 33 % yield in 98:2 er.

Noncovalent Substrate-Directed Enantioselective Heck Reactions: Synthesis of S- and P-Stereogenic Heterocycles.

S- and P-Stereogenic heterocycles were synthesized by a remarkably simple enantioselective Heck desymmetrization reaction based on the unprecedented noncovalent directing effect of S=O and P=O functionalities. Selected prochiral symmetric substrates were efficiently arylated using the recently disclosed chiral PyraBOx ligand under mild and open-flask reaction conditions. Several five-membered aryl- sulfones, sulfoxides, and phosphine oxides were synthesized in good to excellent yields, in good to high diastereoselectivity, and enantiomeric ratios up to 98:2. Theoretical calculations also support the noncovalent directing effect of the S=O and P=O functionalities during the arylation process.

Intermolecular Noncovalent Hydroxy-Directed Enantioselective Heck Desymmetrization of Cyclopentenol: Computationally Driven Synthesis of Highly Functionalized cis-4-Arylcyclopentenol Scaffolds.

New computationally driven protocols for the Heck desymmetrization of 3-cyclopenten-1-ol with aryldiazonium tetrafluoroborates were developed. These new conditions furnished remarkable product selectivity originating from a resident hydroxyl group and the critical choice of the reaction solvent. Mechanistic insights gleaned from theoretical calculations of the putative transition states predicted toluene as an adequate solvent choice to attain high enantioselectivity by strengthening the noncovalent interaction of the substrate hydroxyl group and the chiral cationic palladium catalyst. Laboratory experiments validated the theoretical predictions, and by employing 2% MeOH/toluene as solvent, the Heck-Matsuda reaction provided exclusively the cis-4-arylcyclopentenols 3a-l in good to excellent yields in enantiomeric excesses up to 99%. The performance of the new PyOx ligand (S)-4-tert-butyl-2-(3,5-dichloropyridin-2-yl)-4,5-dihydrooxazole was also successfully evaluated in the Heck-Matsuda desymmetrization of 3-cyclopenten-1-ol. The synthetic potential of these highly functionalized cis-4-arylcyclopentenols is illustrated by a gold-catalyzed synthesis of cyclopenta[b]benzofuran skeletons.

Recent synthetic additions to the visible light photoredox catalysis toolbox.

The boom in visible light photoredox catalysis (VLPC) research has demonstrated that this novel synthetic approach is here to stay. VLPC enables reactive radical intermediates to be catalytically generated at ambient temperature, a feat not generally allowed through traditional pyrolysis- or radical initiator-based methodologies. VLPC has vastly extended the range of substrates and reaction schemes that have been traditionally the domain of radical reactions. In this review the photophysics background of VLPC will be briefly discussed, followed by a report on recent inroads of VLPC into decarboxylative couplings and radical C-H functionalization of aromatic compounds. The bulk of the review will be dedicated to advances in synergistic catalysis involving VLPC, namely the combination of photoredox catalysis with organocatalysis, including ß-functionalization of carbonyl groups, functionalization of weak aliphatic C-H bonds, and anti-Markovnikov hydrofunctionalization of alkenes; dual catalysis with gold or with nickel, photoredox catalysis as an oxidation promoter in transition metal catalysis, and acid-catalyzed enantioselective radical addition to π systems.

Stereoselective synthesis of aryl cyclopentene scaffolds by Heck-Matsuda desymmetrization of 3-cyclopentenol.

A new enantioselective Heck-Matsuda desymmetrization reaction was accomplished by using 3-cyclopentenol to produce chiral five-membered 4-aryl cyclopentenol scaffolds in good yields and high ee's, together with some 3-aryl-cyclopentanones as minor products. Mechanistically, the hydroxyl group of 3-cyclopentenol acts as a directing group and is responsible for the cis- arrangement in the formation of the 4-aryl-cyclopentenols.

Intermolecular enantioselective Heck-Matsuda arylations of acyclic olefins: application to the synthesis of ß-aryl-γ-lactones and ß-aryl aldehydes.

We describe herein a synthetically useful method for the enantioselective intermolecular Heck-Matsuda arylation of acyclic allylic alcohols. Aryldiazonium tetrafluoroborates were applied as arylating agents in the presence of Pd(TFA)2 and a chiral, commercially available, bisoxazoline ligand. The methodology is straightforward, robust, scalable up to a few grams, and of broad scope allowing the synthesis of a range of ß-aryl-carbonyl compounds in good to high enantioselectivities and yields. This new enantioselective Heck-Matsuda arylation allowed the synthesis of ß-aryl-γ-lactones and ß-aryl aldehydes, which play a vital role as key intermediates in the synthesis of the biologically active compounds, such as (R)-baclofen, (R)-rolipram, (S)-curcumene, (S)-dehydrocurcumene, and (S)-tumerone.

"Dba-free" palladium intermediates of the Heck-Matsuda reaction.

The "dba-free" Heck-Matsuda reaction was investigated via direct ESI-MS(/MS) monitoring. Palladium species involved in the reduction of Pd(II) during a Wacker type reaction and several "dba-free" arylpalladium transient complexes were detected and characterized. Based on these findings, a more comprehensible catalytic cycle for this pivotal reaction is suggested.

Stereoselective arylation of substituted cyclopentenes by substrate-directable Heck-Matsuda reactions: a concise total synthesis of the sphingosine 1-phosphate receptor (S1P(1)) agonist VPC01091.

We describe herein an efficient and diastereoselective substrate-directable Heck-Matsuda reaction with nonactivated five-membered olefins. The carbamate acts as the main directing group in the arylation process allowing the synthesis of several functionalized aryl cyclopentenes in good to excellent diastereoselectivities (>85:15) and in isolated yields ranging from 41 to 90%. No double bond isomerizations were observed in these Heck reactions, and the newly created benzylic centers were preserved in all cases examined. The substrate directable Heck arylation approach was successfully applied in a straightforward total synthesis of the sphingosine 1-phosphate receptor-subtype 1 (S1P(1)) agonist VPC01091 by a concise and practical route involving 5 steps in 40% overall yield.

Stereoselective synthesis of unsymmetrical ß,ß-diarylacrylates by a Heck-Matsuda reaction: versatile building blocks for asymmetric synthesis of ß,ß-diphenylpropanoates, 3-aryl-indole, and 4-aryl-3,4-dihydro-quinolin-2-one and formal synthesis of (-)-indatraline.

ß,ß-Disubstituted α,ß-unsaturated esters may serve as valuable derivatives for the preparation of other highly functionalized systems found in many natural products and marketed drugs. The stereoselective synthesis of unsymmetrical ß,ß-diarylacrylate compounds possessing two similar aromatic groups remains a substantial challenge. A simple and convenient stereoselective protocol for the preparation of ß,ß-disubstituted acrylates via a Heck-Matsuda reaction is reported. Good to high yields were accomplished by a "ligand-free" Pd-catalyzed arylation reaction of cinnamate esters with arenediazonium tetrafluoroborates. Both electron-deficient and electron-rich arenediazonium salts could be employed as arylating reagents, and cinnamate esters were generally more reactive when substituted with an electron-donating group. The overall methodology is highly stereoselective, and this attribute was taken advantage of in the asymmetric Cu-catalyzed 1,4 reduction reaction to provide ß,ß-diarylpropanoates in high enantioselectivities. The synthesis of a 3-aryl indole and a chiral 4-aryl-2-quinolone from ß,ß-diarylacrylates was achieved by cyclization in the presence of a diphosphine ligated CuH catalyst. A convenient route for the asymmetric formal synthesis of the psychoactive compound (-)-Indatraline is also presented.

[(2S,5R)-1-Methyl-5-phenyl-pyrrolidin-2-yl]diphenyl-methanol.

In the title compound, C(24)H(25)NO, the phenyl and diphenyl-methanol substituents are syn to each other. The pyrrolidine ring has an envelope conformation with the flap atom being the C atom bearing the phenyl substituent. The hy-droxy group forms an intra-molecular hydrogen bond with the pyrrolidine N atom, and the phenyl rings lie to same side of the mol-ecule. The crystal packing features C-H⋯π inter-actions. Two slightly displaced co-planar orientations were found for one of the phenyl rings; the major component had a site-occupancy factor of 0.782 (15).

In Vitro Anti-Trypanosoma cruzi Activity of Halophytes from Southern Portugal Reloaded: A Special Focus on Sea Fennel (Crithmum maritimum L.).

Marine halophytes are an outstanding reservoir of natural products and several species have anti-infectious traditional uses. However, reports about their potential use against neglected tropical ailments, such as Chagas disease, are scarce. This work evaluated for the first time the in vitro anti-Trypanosoma cruzi activity of extracts from the aromatic and medicinal species Helichrysum italicum subsp. picardii (Boiss. & Reut.) Franco (Asteraceae, everlasting) and Crithmum maritimum L. (Apiaceae, sea fennel). For that purpose, decoctions, tinctures, and essential oils from everlasting's flowers and sea fennel's stems, leaves, and flowers were tested against intracellular amastigotes of two T. cruzi strains. The extract from the sea fennel flower decoction displayed significant anti-trypanosomal activity and no toxicity towards the host cell (EC50 = 17.7 µg/mL, selectivity index > 5.65). Subsequent fractionation of this extract afforded 5 fractions that were re-tested in the same model of anti-parasitic activity. Fraction 1 was the most active and selective (EC50 = 0.47 µg/mL, selectivity index = 59.6) and was submitted to preparative thin-layer chromatography. One major compound was identified, falcarindiol, which was likely the one responsible for the observed anti-trypanosomal activity. This was confirmed using a commercially sourced molecule. Target-fishing studies showed falcarindiol as a ligand of T. cruzi spermidine synthase, pointing to a potential enzyme-inhibiting anti-trypanosomal mechanism of action. Overall, this work shows that sea fennel can provide effective anti-parasitic molecule(s) with potential pharmacological applications in the treatment of CD.

Ethyl 3,4-bis-(acet-yloxy)-2-(4-meth-oxy-phen-yl)pyrrol-idine-1-carboxyl-ate.

The title pyrrolidine compound, C18H23NO7, is a tetra-substituted species in which the five-membered ring has a twisted conformation with the twist occurring in the C-C bond bearing the adjacent acet-yloxy substituents; the Cm-Ca-Ca-Cp torsion angle is -40.76 (18)° [m = methyl-ene, a = acet-yloxy and p = phen-yl]. The N atom, which is sp 2-hybridized [sum of bond angles = 359.4°], bears an ethyl-carboxyl-ate substitutent and is connected to a methyl-ene-C atom on one side and a carbon atom bearing a 4-meth-oxy-phenyl group on the other side. Minor disorder is noted in the ethyl-carboxyl-ate substituent as well as in one of the acet-yloxy groups; the major components of the disorder have site occupancies of 0.729 (9) and 0.62 (3), respectively. The most notable feature of the mol-ecular packing is the formation of helical, supra-molecular chains aligned along the b-axis direction whereby the carbonyl-O atom not involved in a disordered residue accepts C-H⋯O inter-actions from methyl-ene-H and two-C atom separated methine-H atoms to form a six-membered {⋯HCCCH⋯O} synthon.

4-Nitro-benzyl 3,4-bis-(acet-yloxy)-2-(4-meth-oxy-phen-yl)pyrrolidine-1-carboxyl-ate: crystal structure, Hirshfeld surface analysis and computational chemistry.

The title compound, C23H24N2O9, is a tetra-substituted pyrrolidine derivative with a twisted conformation, with the twist evident in the C-C bond bearing the adjacent acet-yloxy substituents. These are flanked on one side by a C-bound 4-meth-oxy-phen-yl group and on the other by a methyl-ene group. The almost sp 2-N atom [sum of angles = 357°] bears a 4-nitro-benzyl-oxycarbonyl substituent. In the crystal, ring-methyl-ene-C-H⋯O(acet-yloxy-carbon-yl) and methyl-ene-C-H⋯O(carbon-yl) inter-actions lead to supra-molecular layers lying parallel to (01); the layers stack without directional inter-actions between them. The analysis of the calculated Hirshfeld surfaces indicates the combined importance of H⋯H (42.3%), H⋯O/O⋯H (37.3%) and H⋯C/C⋯H (14.9%) surface contacts. Further, the inter-action energies, largely dominated by the dispersive term, point to the stabilizing influence of H⋯H and O⋯O contacts in the inter-layer region.

1-Ethyl 2-methyl 3,4-bis-(acet-yloxy)pyrrolidine-1,2-di-carboxyl-ate: crystal structure, Hirshfeld surface analysis and computational chemistry.

The title compound, C13H19NO8, is based on a tetra-substituted pyrrolidine ring, which has a twisted conformation about the central C-C bond; the Cm-Ca-Ca-Cme torsion angle is 38.26 (15)° [m = methyl-carboxyl-ate, a = acet-yloxy and me = methyl-ene]. While the N-bound ethyl-carboxyl-ate group occupies an equatorial position, the remaining substituents occupy axial positions. In the crystal, supra-molecular double-layers are formed by weak methyl- and methyl-ene-C-H⋯O(carbon-yl) inter-actions involving all four carbonyl-O atoms. The two-dimensional arrays stack along the c axis without directional inter-actions between them. The Hirshfeld surface is dominated by H⋯H (55.7%) and H⋯C/C⋯H (37.0%) contacts; H⋯H contacts are noted in the inter-double-layer region. The inter-action energy calculations point to the importance of the dispersion energy term in the stabilization of the crystal.

(4-Nitro-phen-yl)methyl 2,3-di-hydro-1H-pyrrole-1-carboxyl-ate: crystal structure and Hirshfeld analysis.

In the title compound, C12H12N2O4, the di-hydro-pyrrole ring is almost planar (r.m.s. deviation = 0.0049 Å) and is nearly coplanar with the adjacent C2O2 residue [dihedral angle = 4.56 (9)°], which links to the 4-nitro-benzene substituent [dihedral angle = 4.58 (8)°]. The mol-ecule is concave, with the outer rings lying to the same side of the central C2O2 residue and being inclined to each other [dihedral angle = 8.30 (7)°]. In the crystal, supra-molecular layers parallel to (10-5) are sustained by nitro-benzene-C-H⋯O(carbon-yl) and pyrrole-C-H⋯O(nitro) inter-actions. The layers are connected into a three-dimensional architecture by π(pyrrole)-π(nitro-benzene) stacking [inter-centroid separation = 3.7414 (10) Å] and nitro-O⋯π(pyrrole) inter-actions.

(1R,2S,5R)-5-Methyl-2-[2-(4-nitro-phen-yl)propan-2-yl]cyclo-hexyl 2-(4-meth-oxy-phen-yl)-2,5-di-hydro-1H-pyrrole-1-carboxyl-ate: crystal structure and Hirshfeld analysis.

In the title compound, C28H34N2O5, the adjacent ester and nitro-benzene substituents are connected via an intra-molecular methyl-ene-C-H⋯π(nitrobenzene) inter-action and the mol-ecule approximates to a U-shape. The di-hydro-pyrrole ring (r.m.s. deviation = 0.003 Å) is almost co-planar with the carboxyl-ate residue [Cm-N-C1-Oc (m = methine, c = carbox-yl) torsion angle = 1.8 (4)°] but is orthogonal to the 4-meth-oxy-benzene ring [dihedral angle = 84.34 (17)°]. In the crystal, methyl-ene-C-H⋯O(carbon-yl) inter-actions lead to linear supra-molecular chains along the b-axis direction, which pack without directional inter-actions between them. The analysis of the calculated Hirshfeld surface points to the importance of weak inter-atomic H⋯H, O⋯H/H⋯O and C⋯H/H⋯C contacts in the crystal.

Ethyl 2-(4-meth-oxy-phen-yl)-6-oxa-3-aza-bicyclo[3.1.0]hexane-3-carboxyl-ate: crystal structure and Hirshfeld analysis.

The title compound, C14H17NO4, features an epoxide-O atom fused to a pyrrolidyl ring, the latter having an envelope conformation with the N atom being the flap. The 4-meth-oxy-phenyl group is orthogonal to [dihedral angle = 85.02 (6)°] and lies to the opposite side of the five-membered ring to the epoxide O atom, while the N-bound ethyl ester group (r.m.s. deviation of the five fitted atoms = 0.0187 Å) is twisted with respect to the ring [dihedral angle = 17.23 (9)°]. The most prominent inter-actions in the crystal are of the type methine-C-H⋯O(carbon-yl) and these lead to the formation of linear supra-molecular chains along the c axis; weak benzene-C-H⋯O(epoxide) and methine-C-H⋯O(meth-oxy) inter-actions connect these into a three-dimensional architecture. The analysis of the Hirshfeld surface confirms the presence of C-H⋯O inter-actions in the crystal, but also the dominance of H⋯H dispersion contacts.

3-Hy-droxy-2-phenyl-2,3,3a,7a-tetra-hydro-1H,5H-pyrano[3,2-b]pyrrol-5-one: crystal structure and Hirshfeld surface analysis.

The title isoaltholactone derivative, C13H13NO3, has an NH group in place of the ether-O atom in the five-membered ring of the natural product. The five-membered ring is twisted about the N-C bond linking it to the six-membered ring, which has a half-chair conformation with the O atom connected to the ether-O atom lying above the plane defined by the remaining atoms. The dihedral angle between the mean planes of the rings comprising the fused-ring system is 75.10 (8)°. In the crystal, hy-droxy-O-H⋯N(amine) hydrogen bonding sustains linear supra-molecular chains along the a axis. Chains are linked into a three-dimensional architecture via amine-N-H⋯π(phen-yl) and phenyl-C-H⋯O(hy-droxy) inter-actions. The influence of the amine-N-H⋯π(phen-yl) contact on the mol-ecular packing is revealed by an analysis of the Hirshfeld surface.

Probing the stereoselectivity of the Heck arylation of endocyclic enecarbamates with diazonium salts. Concise syntheses of (2S,5R)-phenylproline methyl ester and Schramm's C-azanucleoside.

[reaction: see text] The diastereoselectivity of the Heck arylation of several chiral, nonracemic, five-membered endocyclic enecarbamates with aryldiazonium tetrafluoroborates was evaluated. The cis selectivity observed for some enecarbamates bearing coordinating groups was explored in the concise synthesis of the (2S,5R)-(+)-phenylproline methyl ester, a scaffold for the nonpeptide cholecystokinin antagonist (+)-RP 66803, and in the synthesis of Schramm's potent antiprotozoan C-azanucleoside.