Palladium‐Catalyzed Fluoride‐Free Cross‐Coupling of Intramolecularly Activated Alkenylsilanes and Alkenylgermanes: Synthesis of Tamoxifen as a Synthetic Application

We have demonstrated that intramolecular hypercoordination of a carboxylic acid is a powerful activation strategy for the palladium‐catalyzed cross‐coupling reaction of trialkyl(vinyl)silanes and trialkyl(vinyl)germanes under fluoride‐free conditions. Z‐β‐Trialkylsilyl‐ and Z‐β‐trialkylgermylacrylic acids, synthesized stereoselectively by olefination with ynolates, are highly stable and useful reagents for cross‐coupling with a variety of aryl iodides to provide tetrasubstituted olefins possessing different carbon substituents in a stereocontrolled and diversity‐oriented manner. An application to a stereoselective synthesis of (Z)‐tamoxifen is also reported.     

Arylethyne Bromoboration–Negishi Coupling Route to E‐ or Z‐Aryl‐Substituted Trisubstituted Alkenes of ≥98% Isomeric Purity. New Horizon in the Highly Selective Synthesis of Trisubstituted Alkenes

The hitherto unprecedented palladium‐catalyzed cross‐coupling of (Z)‐β‐bromo‐β‐arylethenylboranes can be made to proceed satisfactorily through (1) the use of highly catalytically active bis(tri‐tert‐butylphosphine)palladium or dichloro[N,N‐bis‐(2,6‐diisopropylphenyl)imidazol‐2‐yl](m‐chloropyridine)palladium and (2) conversion of the dibromoboryl group to the (pinacol)boryl group. Thus, a wide variety of carbon groups can be used to substitute bromine in ≥98% stereo‐ and regioselectivity, while suppressing the otherwise dominant β‐debromoboration. Together with the alkylethyne‐based protocols, the alkyne bromoboration–Negishi coupling tandem process has emerged as the most widely applicable and highly selective route to trisubstituted alkenes including those that are otherwise difficult to access.     

A New Type of Stereoselectivity in Baeyer–Villiger Reactions: Access to E‐ and Z‐Olefins

A new concept for accessing configurationally defined trisubstituted olefins has been developed. Starting from a common ketone precursor of the type 4‐ethylidenecyclohexanone, Baeyer–Villiger monooxygenases are employed as catalysts in diastereoselective Baeyer–Villiger reactions leading to the corresponding E‐ or Z‐configurated lactones. Wild‐type cyclohexanone monooxygenase (CHMO) as catalyst delivers the E‐isomers and a directed evolution mutant the opposite Z‐isomers. Subsequent transition metal‐catalyzed chemical transformations of a key product containing a vinyl bromide moiety provide a variety of different trisubstituted E‐ or Z‐olefins. A model based on QM/MM sheds light on the origin of this unusual type of diastereoselectivity. In contrast to this biocatalytic approach, traditional Baeyer–Villiger reagents such as m‐CPBA fail to show any selectivity, 1:1 mixtures of E‐ and Z‐olefins being formed.     

Nickel‐ or Palladium‐Catalyzed Stereoselective Synthesis of Tetrasubstituted Olefinic Indolines‐Fused Triazoles: Extension to the Spiroindoline Core

A nickel‐ or palladium‐catalyzed cascade approach to afford indolines‐fused triazoles with tetrasubstituted olefins in good yields with excellent control of regio‐ and stereoselectivity is described. We have also discussed the synthesis of unsaturated carbonyl species when the alkyne was appended to an alkyl chain. The synthetic methodology has been extended to construct the biologically active spiroindoline core via a vinylcylopropane (VCP) intermediate. The synthesized tetrasubstituted scaffolds were investigated for their photophysical properties and all of the them exhibited good absorption and fluorescence emission in the UV‐visible region.

     

Regio‐ and Stereoselective Synthesis of Tri‐ and Tetrasubstituted Enamides via Palladium‐Catalyzed Silaboration of Ynamides

The palladium‐catalyzed silaboration of ynamides is demonstrated. The silaboration proceeds in a highly regioselective manner to give the corresponding tri‐ and tetrasubstituted enamide derivatives having both a silyl group and a boryl group on the alkene. Furthermore, the silaborated enamide could be utilized as a coupling partner in Suzuki–Miyaura coupling with aryl iodides to give the corresponding cross‐coupling product in good yield.     

Palladium‐Catalyzed Synthesis of Functional Tetralins via Benzylic Activation

2‐Monosubstituted, 2,2‐ and 2,3‐disubstituted tetralin derivatives have been synthesized from α,α′‐dihalo‐o‐xylenes and activated olefins using a palladium catalyst under basic conditions. The effects of temperature, base, palladium precursor and solvent have been fully explored, and this new catalytic reaction has been extended to a variety of substrates.     

Thiosemicarbazone Salicylaldiminato‐Palladium(II)‐Catalyzed Mizoroki–Heck Reactions

Four tridentate thiosemicarbazone salicylaldiminato‐palladium(II) complexes of the general formula [Pd(saltsc‐R)PPh₃] [saltsc=salicylaldehyde thiosemicarbazone; R=H ( 1 ), 3‐tert‐butyl ( 2 ), 3‐methoxy ( 3 ), 5‐chloro ( 4 )], have been evaluated as catalyst precursors for the Mizoroki–Heck coupling reaction between a variety of electron‐rich and electron‐poor aryl halides and olefins. The palladium complexes (0.1–1 mol% loading) were found to effectively catalyze these reactions with high yields being obtained when aryl iodides and aryl bromides were utilized. The effects of base, catalyst loading, reaction temperature and reaction time on the catalytic activity of the most active complex were also investigated.     

sp3‐sp2 C‐C Bond Formation via Brønsted Acid Trifluoromethanesulfonic Acid‐Catalyzed Direct Coupling Reaction of Alcohols and Alkenes

A novel and efficient trifluoromethanesulfonic acid‐catalyzed sp³‐sp² C C bond formation reaction through the direct coupling of alcohols with alkenes has been realized under mild conditions. The present protocol provides an attractive approach to a diverse range of polysubstituted olefins in good to excellent yields with high stereo‐ and regioselectivities.     

Copper‐Mediated and ‐Catalyzed o‐DPPB‐Directed Allylic Substitution

Complete control of chemo‐, regio‐ and stereoselectivity in the course of copper‐catalyzed and ‐mediated allylic substitution could be obtained with the ortho‐diphenylphosphanyl (o‐DPPB) function as a reagent‐directing leaving group. Complete chirality transfer by way of a syn‐addition process has been achieved for cyclic and acyclic systems. Readily available Grignard reagents may be employed as nucleophiles and the directing o‐DPPB group can be recovered quantitatively. The reaction requires neither cooling nor an excess of organometallic reagent.     

Palladium Nanoparticles in Suzuki Cross‐Couplings: Tapping into the Potential of Tris‐Imidazolium Salts for Nanoparticle Stabilization

Inspired by the proclivity of various palladium sources to form nanoparticles in imidazolium‐based ionic liquids, we now report that tris‐imidazolium salts bearing hexadecyl chains and a bridging mesitylene moiety are potent stabilizers of palladium nanoparticles efficiently prepared via a Chaudret‐type hydrogenation of the bis(dibenzylideneacetone)palladium(0). The palladium nanoparticles have been isolated in pure form and characterized by ¹H nuclear magnetic resonance, transmission electron microscopy, electron diffraction and dynamic light scattering. The new materials proved effective in Suzuki cross‐coupling at a loading of 0.2% palladium. Thus, using a tris‐imidazolium iodide‐palladium material, a series of biaryl products has been prepared starting from aryl bromides and some activated chlorides. The possibility that this catalytic activity might be due to the formation of palladium N‐heterocyclic carbenes has been addressed through solid state ¹³C NMR and the synthesis of an imidazolium analogue in which the acidic 2‐H was replaced with a methyl group.     

Palladium‐Catalyzed Domino Cyclization (5‐exo/3‐exo), Ring‐ Expansion by Palladium Rearrangement,and Aromatization: An Expedient Synthesis of 4‐Arylnicotinates from Morita–Baylis–Hillman Adducts

Various 4‐arylnicotinate derivatives were synthesized via a palladium‐catalyzed cascade reaction of N‐(2‐bromoallyl)‐N‐cinnamyltosylamides in a one‐pot procedure in good yields. The reaction involves a domino 5‐exo/3‐exo carbopalladation, ring‐expansion by palladium rearrangement, and an aromatization process.     

Palladium‐Catalyzed Highly Chemo‐, Regio‐ and Stereoselective Synthesis of Eight‐ to Ten‐Membered Lactones from Allenyl 3‐Oxoalkanoates and Organic Halides

A highly chemo‐, regio‐, and stereoselective synthesis of eight‐ to ten‐membered lactones via the coupling cyclization of readily available allenyl 3‐oxoalkanoates and organic halides through an anti‐π‐allylic palladium intermediate is reported. The yields ranged from moderate to good.     

Selective Aryl α‐Diimine/Palladium‐Catalyzed Bis‐Alkoxy‐ carbonylation of Olefins for the Synthesis of Substituted Succinic Diesters

Aryl α‐diimine derivatives have been used, for the first time, as efficient new ligands for the palladium‐catalyzed oxidative bis‐alkoxycarbonylation reaction of olefins. The most active catalyst was formed in situ from bis(9‐anthryl)‐2,3‐dimethyl‐1,4‐diazabutadiene and palladium(II) trifluoroacetate [Pd(TFA)₂]. This catalytic system was able to selectively convert olefins into succinic diesters in good yields (up to 97%) and low catalyst loading (up to 0.5 mol%) under mild reaction conditions [4 bar of carbon monoxide (CO) at 20 °C in the presence of p‐toluenesulphonic acid as additive and p‐benzoquinone as oxidant]. The optimized conditions could be successfully applied to both aromatic and aliphatic olefins, by using methanol, benzyl alcohol or isopropyl alcohol as nucleophiles.

     

Sulfonated N‐Heterocyclic Carbenes for Pd‐Catalyzed Sonogashira and Suzuki–Miyaura Coupling in Aqueous Solvents

The reactions of the N,N′‐diarylimidazolium and N,N′‐diarylimidazolinium salts with chlorosulfonic acid result in the formation of the respective disulfonated N‐heterocyclic carbene (NHC) precursors in reasonable yields (46–77%). Water‐soluble palladium catalyst complexes, in situ obtained from the respective sulfonated imidazolinium salt, sodium tetrachloropalladate (Na₂PdCl₄) and potassium hydroxide (KOH) in water, were successfully applied in the copper‐free Sonogashira coupling reaction in isopropyl alcohol/water mixtures using 0.2 mol% catalyst loading. The preformed (disulfonatedNHC)PdCl(cinnamyl) complex was used in aqueous Suzuki–Miyaura reactions at 0.1 mol% catalyst loading. The coupling protocol reported here is very useful for Sonogashira reactions of N‐ and S‐heterocyclic aryl bromides and chlorides with aryl‐ and alkylacetylenes.     

Hybrid Organic‐Inorganic Materials Derived from a Monosilylated Hoveyda‐type Ligand as Recyclable Diene and Enyne Metathesis Catalysts

The synthesis of a monosilylated Hoveyda‐type monomer is described as well as the preparation of several organic‐inorganic hybrid materials derived from it by sol‐gel processes and by anchoring to commercial silica gel and MCM‐41. The resulting materials were treated with first and/or second generation Grubbs’ catalyst to generate Hoveyda–Grubbs’ type alkylidene ruthenium complexes covalently bonded to the silica matrix. These materials are efficient recyclable catalysts for the ring‐closing metathesis reaction of dienes and enynes, even for the formation of tri‐ and tetrasubstituted olefins.     

Palladium‐Catalyzed Regioselective and Stereoselective Oxidative Heck Arylation of Allylamines with Arylboronic Acids

A general and convenient palladium‐catalyzed oxidative Heck arylation of both N‐protected and N,N‐diprotected allylic amines with arylboronic acids under mild conditions has been developed. The catalyst system, consisting of Pd(OAc)₂ (palladium acetate), AgOAc (silver acetate) and KHF₂ (potassium hydrogen fluoride), could efficiently catalyze the coupling reaction in acetone without the aid of any ligand, leading exclusively to the γ‐arylated allylic amine products in good to excellent yields. This method is highlighted with excellent regio‐ and stereocontrol and remarkable functional group tolerance. The carbamate moiety in allylic amine substrates is of crucial importance to the catalytic performance, and the chelation between the carbonyl O (oxygen) and Pd (palladium) atoms is believed to be responsible for the high regioselectivity and stereoselectivity observed.     

Selective Palladium‐Catalyzed Suzuki–Miyaura Reactions of Polyhalogenated Heteroarenes

The palladium‐catalyzed Suzuki–Miyaura reaction of multiply halogenated, electron‐rich and electron‐deficient heteroarenes is one of the most reliable and environmentally friendly tools for installing a wide range of non‐functionalized and functionalized carbon substituents onto heteroaromatic systems with exquisite chemo‐ and site‐selectivity. For substrates with different halogen groups the chemoselectivity of the Suzuki–Miyaura reactions has been found to be dependent on the reactivity difference between the halogens. However, the hardest achievement of selectivity in Suzuki–Miyaura monocouplings involving polyhalogenated heteroarenes with identical halogen atoms has been shown to be dominated by steric and electronic effects and the presence of directing groups at positions neighbouring the reaction sites. Moreover, in the case of symmetrically substituted dihaloheteroarenes with identical halogen atoms, highly selective monocoupling reactions have often been achieved only after a careful optimization of reaction parameters including the catalyst precursor, base, solvent, and the molar ratio between electrophile and organoboron reagent. This critical review with 341 references covers developments on the chemo‐ and site‐selective Suzuki–Miyaura monocoupling reactions of polyhalogenated heteroarenes with different or identical halogen atoms. It also includes the synthesis of polysubstituted heteroarenes, not easily accessible by other means, via consecutive monocoupling reactions and/or a more synthetically valuable approach involving one‐pot polycoupling reactions.     

Palladium Nanoparticles Immobilized on Nano‐Silica Triazine Dendritic Polymer (Pdnp‐nSTDP): An Efficient and Reusable Catalyst for Suzuki–Miyaura Cross‐Coupling and Heck Reactions

A new catalyst based on palladium nanoparticles immobilized on nano‐silica triazine dendritic polymer (Pd_np‐nSTDP) was synthesized and characterized by FT‐IR spectroscopy, thermogravimetric analysis, field emission scanning electron microscopy, energy dispersive X‐ray, transmission electron microscopy and elemental analysis. The size of the palladium nanoparticles was determined to be 3.1±0.5 nm. This catalytic system showed high activity in the Suzuki–Miyaura cross‐coupling of aryl iodides, bromides and chlorides with arylboronic acids and also in the Heck reaction of these aryl halides with styrenes. These reactions were best performed in a dimethylformamide (DMF)/water mixture (1:3) in the presence of only 0.006 mol% and 0.01 mol% of the catalyst, respectively, under conventional conditions and microwave irradiation to afford the desired coupling products in high yields. The Pd_np‐nSTDP was also used as an efficient catalyst for the preparation of a series of star‐ and banana‐shaped compounds with a benzene, pyridine, pyrimidine or 1,3,5‐triazine unit as the central core. Moreover, the catalyst could be recovered easily and reused several times without any considerable loss of its catalytic activity.     

Stereoselective Synthesis of 3‐Hydroxy‐4‐arylcyclopentanones and 4‐Arylcyclopentenones through a Heck–Matsuda Desymmetrization of meso cis‐4‐Cyclopentene‐1,3‐diol

A new palladium‐catalyzed route to 3‐hydroxy‐4‐arylcyclopentanones and 4‐arylcyclopentenones in a diastereo‐ and enantioselective manner by a Heck–Matsuda desymmetrization was achieved from the commercially available meso cis‐4‐cyclopentene‐1,3‐diol. This method is highly practical, mild, high yielding and is carried out under “open vessel” conditions. Protected and unprotected substrates provide distinct products bearing considerable value as synthetic scaffolds for the synthesis of natural and unnatural bioactive compounds containing a five‐membered ring.

     

Highly (≥98%) Stereo‐ and Regioselective Trisubstituted Alkene Synthesis of Wide Applicability via 1‐Halo‐1‐alkyne Hydro‐ boration–Tandem Negishi–Suzuki Coupling or Organoborate Migratory Insertion

(Z)‐1‐Halo‐1‐alkenylboranes ( 7 ), preparable in 80–90% yields as ≥98% isomerically pure compounds via hydroboration of 1‐halo‐1‐alkynes, have been converted to a wide range of trisubstituted alkenes via three different routes in the tail‐to‐head ( T ‐to‐ H ) direction, i.e., (i) palladium‐catalyzed Negishi–Suzuki tandem alkenylation, (ii) treatment with organolithium or Grignard reagents to generate α‐bromo‐1‐alkenylboronate complexes that can undergo migratory insertion of a carbon group (R²) to form (E)‐alkenylboranes with inversion of alkene configuration (≥98% inversion), followed by fluoride‐promoted Suzuki alkenylation, and (iii) Negishi coupling to generate (Z)‐alkenylboranes in ≥98% retention of configuration, followed by treatment with organolithium or Grignard reagents to produce trisubstituted alkenes with reversed stereo configurations. The synthetic utility of the present methodology has been demonstrated in the highly selective synthesis of the side chain of scyphostatin in 28% yield over nine steps in the longest linear sequence from allyl alcohol. Thus, this new tandem protocol has been emerged as the most widely applicable and highly selective route to trisubstituted alkenes including those that are otherwise difficult to prepare.