Control of N‐Heterocyclic Carbene Catalyzed Reactions of Enals: Asymmetric Synthesis of Oxindole‐γ‐Amino Acid Derivatives

A strategy to control the switch between a non‐cycloaddition reaction and a cycloaddition reaction of enals, using N‐heterocyclic carbene (NHC) catalyisis, has been developed. The new scalable protocol leads to γ‐amino‐acid esters bearing a tetrasubstituted stereocenter in good yields and high stereoselectivities by homo‐Mannich reactions of enals and isatin‐derived ketimines. By simply changing the N‐ketimine substituent to an ortho‐hydroxy phenyl group, the corresponding spirocyclic oxindolo‐γ‐lactams are obtained.     

One‐Pot Synthesis of Aliphatic Nitro Compounds by Michael/retro‐Claisen Fragmentation Domino Reaction

A novel and concise method for the construction of γ‐nitro ketones and 1,3‐dinitro compounds with chemoselective acyl transfer has been presented under basic conditions via one‐pot reactions. These reactions feature high atom‐ and step‐economic possess, mild condition and simple operation for one‐pot synthesis of aliphatic nitro compounds. This protocol provides the products in good yields. The possible reaction mechanism has also been proposed.     

Tandem Cross‐Coupling/Spirocyclization/Mannich‐Type Reactions of 3‐(2‐Isocyanoethyl)indoles with Diazo Compounds toward Polycyclic Spiroindolines

Tandem reactions of Pd‐catalyzed cross‐coupling of 3‐(2‐isocyanoethyl)indoles with diazoacetates and subsequent spirocyclization/Mannich‐type reaction have been developed to assemble polycyclic spiroindoline skeletons. Formation of spiroindolenines has been proven as the crucial step for the following Mannich‐type cyclization reaction. Accordingly, a novel approach on chiral phosphoric acid catalyzed Mannich‐type cyclization toward the formation of diastereomerically and enantiomerically enriched pentacyclic spiroindolines has been established. Moreover, the products of the reaction are versatile building blocks in synthetic chemistry, as demonstrated by the synthesis of the key framework of aspidosperma and kopsia alkaloids.     

Asymmetric Synthesis of Spirocyclic β‐Lactams through Copper‐Catalyzed Kinugasa/Michael Domino Reactions

The first copper‐catalyzed highly chemo‐, regio‐, diastereo‐, and enantioselective Kinugasa/Michael domino reaction for the desymmetrization of prochiral cyclohexadienones is described. In the presence of a chiral copper catalyst, alkyne‐tethered cyclohexadienones couple with nitrones to generate the chiral spirocyclic lactams with excellent stereoselectivity (up to 97 % ee, >20:1 dr). The new method provides direct access to versatile highly functionalized spirocyclic β‐lactams possessing four contiguous stereocenters, including one quaternary and one tetra‐substituted stereocenter.     

Highly Chemoselective Synthesis of Indolizidine Lactams by SmI2‐Induced Umpolung of the Amide Bond via Aminoketyl Radicals: Efficient Entry to Alkaloid Scaffolds

Samarium(II) iodide enables a wide range of highly chemoselective umpolung radical transformations proceeding by electron transfer to carbonyl groups; however, cyclizations of important nitrogen‐containing precursors have proven limited due to their prohibitive redox potential. Herein, we report the first reductive cyclizations of unactivated cyclic imides onto N‐tethered olefins using SmI₂/H₂O. This new umpolung protocol leads to the rapid synthesis of nitrogen‐containing heterocycles that are of particular significance as precursors to pharmaceutical pharmacophores and numerous classes of alkaloids. The reaction conditions tolerate a wide range of functional groups. Excellent chemoselectivity is observed in the cyclization over amide and ester functional groups. Such unconventional reactivity has important implications for the design and optimization of new bond‐forming reactions by umpolung radical processes. The reaction advances the SmI₂ cyclization platform to the challenging unactivated N‐tethered acyl‐type radical precursors to access nitrogen‐containing architectures.     

Total Synthesis of (−)‐Cephalotaxine and (−)‐Homoharringtonine via Furan Oxidation–Transannular Mannich Cyclization

Homoharringtonine and its congener cephalotaxine were synthesized. Oxidative ring‐opening of a furan unveils an amine‐tethered dicarbonyl, which undergoes spontaneous transannular Mannich cyclization. The cascade builds the full cephalotaxine substructure in a single operation in 60 % yield. A Noyori reduction enabled synthesis of the title compounds with excellent enantioselectivity (k_rel=278).     

Palladium(0)‐Catalyzed Intermolecular Carbocyclization of (1,n)‐Diynes and Bromophenols: An Efficient Route to Tricyclic Scaffolds

A novel palladium(0)‐catalyzed dearomative cyclization reaction of bromophenols with (1,n)‐diynes has been developed for building two new types of tricyclic architectures containing a quaternary carbon center. This method employs inexpensive bromophenols, and easily accessible tethered diynes. It exhibits a broad substrate scope and tolerates various functional groups. Preliminary results with commercially available chiral ligands indicate that enantioselective variants are feasible for both cyclization processes.     

Pd(II)‐Catalyzed Tandem Enantioselective Methylene C(sp3)−H Alkenylation–Aza‐Wacker Cyclization to Access β‐Stereogenic γ‐Lactams

Herein, we describe an unprecedented cascade reaction to β‐stereogenic γ‐lactams involving Pd(II)‐catalyzed enantioselective aliphatic methylene C(sp³)?H alkenylation–aza‐Wacker cyclization through syn‐aminopalladation. Readily available 3,3′‐substituted BINOLs are used as chiral ligands, providing the corresponding γ‐lactams with broad scope and high enantioselectivities (up to 98 % ee).     

Utility of Ketonic Mannich Bases in Synthesis of Some New Functionalized 2‐Pyrazolines

The styryl ketonic Mannich base 2 has been used as a precursor in the synthesis of 2‐pyrazolines having a basic side chain at C‐3 and a phenolic Mannich base at C‐5. Treatment of the bis(styryl ketonic bases) 6a and 8a with phenylhydrazine affords the bis(3‐functionalized 2‐pyrazolines) 7 and 9 . The transamination between the styryl keto base 10 and 4‐aminoantipyrine leads to 12 , which reacts with piperazine to give 13 . N‐Nitrosation of the sec‐Mannich bases 15a – d followed by reductive cyclization affords 2‐pyrazolines 17a – d . The keto base 14b has been used for the synthesis of 2‐pyrazolines having a phenolic Mannich base at C‐3 and its reaction with 3,5‐dimethyl‐1H‐pyrazole affords 23 . The alkylation of 3‐methyl‐1‐phenyl‐2‐pyrazolin‐5‐one with the bis(Mannich base) 25 was investigated.     

Protonation‐Assisted Conjugate Addition of Axially Chiral Enolates: Asymmetric Synthesis of Multisubstituted β‐Lactams from α‐Amino Acids

β‐Lactams with contiguous tetra‐ and trisubstituted carbon centers were prepared in a highly enantioselective manner through 4‐exo‐trig cyclization of axially chiral enolates generated from readily available α‐amino acids. Use of a weak base (metal carbonate) in a protic solvent (EtOH) is the key to the smooth production of β‐lactams. Use of the weak base is expected to generate the axially chiral enolates in a very low concentration, which undergo intramolecular conjugate addition without suffering intermolecular side reactions. Highly strained β‐lactam enolates thus formed through reversible intramolecular conjugate addition (4‐exo‐trig cyclization) of axially chiral enolates undergo prompt protonation by EtOH in the reaction media (not during the work‐up procedure) to give β‐lactams in up to 97 % ee.     

Generation and Rearrangement of N,O‐Dialkenylhydroxylamines for the Synthesis of 2‐Aminotetrahydrofurans

A new diastereoselective route to 2‐aminotetrahydrofurans has been developed from N,O‐dialkenylhydroxylamines. These intermediates undergo a spontaneous C?C bond‐forming [3,3]‐sigmatropic rearrangement followed by a C?O bond‐forming cyclization. A copper‐catalyzed N‐alkenylation of an N‐Boc‐hydroxylamine with alkenyl iodides, and a base‐promoted addition of the resulting N‐hydroxyenamines to an electron‐deficient allene, provide modular access to these novel rearrangement precursors. The scope of this de novo synthesis of simple nucleoside analogues has been explored to reveal trends in diastereoselectivity and reactivity. In addition, a base‐promoted ring‐opening and Mannich reaction has been discovered to covert 2‐aminotetrahydrofurans to cyclopentyl β‐aminoacid derivatives or cyclopentenones.     

Asymmetric Ring Opening/Cyclization/Retro‐Mannich Reaction of Cyclopropyl Ketones with Aryl 1,2‐Diamines for the Synthesis of Benzimidazole Derivatives

A highly efficient asymmetric ring‐opening/cyclization/retro‐Mannich reaction of cyclopropyl ketones with aryl 1,2‐diamines has been realized using a chiral N,N′‐dioxide/Sc^III catalyst. Benzimidazoles containing chiral side chains were generated under mild reaction conditions in excellent outcomes (up to 99 % yield and 97 % ee). This method also provides efficient access to chiral benzimidazole‐substituted amide and cycloheptene derivatives.     

Stereoselective Synthesis of Tetrahydrofuran Spiro‐β‐Lactams by Ru‐Catalyzed Metathesis of 7‐Oxabicyclo[2.2.1]heptenes

A new method for the synthesis of spiro‐β‐lactams tethered to tetrahydrofuran rings is described. The procedure is based on Ru‐catalyzed metathesis sequences with oxanorbornene precursors easily obtained by the Staudinger [2+2] cycloaddition of related imines.     

(±)‐2‐Aryl‐2,3‐dihydro‐4(1H)‐quinolinones by a tandem reduction–Michael addition reaction

An efficient synthesis of (±)‐2‐aryl‐2,3‐dihydro‐4(1H)‐quinolinones has been developed from chalcones prepared from 2′‐nitroacetophenone and a series of substituted benzaldehydes. The cyclization sequence is initiated by reduction of the nitro group under dissolving metal conditions using iron powder in concentrated hydrochloric acid. Milder conditions, using acetic acid or acetic acid–phosphoric acid as the reaction medium, were less satisfactory. Procedural details as well as a mechanistic discussion and reaction optimization studies are presented. J. Heterocyclic Chem., (2011).     

Chemoselective Aromatic Azido Reduction with Concomitant Aliphatic Azide Employing Al/Gd Triflates/NaI and ESI‐MS Mechanistic Studies

Aluminium and gadolinium triflates catalyze the chemoselective reduction of aromatic azides to the corresponding amines in combination with sodium iodide. This mild chemoselective method has been applied to the synthesis of various aryl amines, C2‐azido‐substituted pyrrolo[2,1‐c][1,4]benzodiazepines, and fused[2,1‐b]quinazolinones by an intramolecular azido reduction tandem cyclization reaction. Interestingly, this methodology selectively reduces aryl azides with enhanced yields and proceeds in shorter reaction times than previous strategies. The mechanistic aspects have been investigated and the intermediates associated with this selective transformation have been intercepted and characterized by online monitoring of the reaction by ESI‐MS.     

A Versatile Synthesis of β‐Lactam‐Fused Oxacycles through the Palladium‐Catalyzed Chemo‐, Regio‐, and Diastereoselective Cyclization of Allenic Diols

Chemo‐, regio‐ and stereocontrolled palladium‐catalyzed preparations of enantiopure morpholines, oxocines, and dioxonines have been developed starting from 2‐azetidinone‐tethered γ,δ‐, δ,ε‐, and ε,ζ‐allendiols. The palladium‐catalyzed cyclizative coupling reaction of γ,δ‐allendiols 2 with allyl bromide or lithium bromide was effective as 8‐endo cyclization by attack of the primary hydroxy group to the terminal allene carbon to afford enantiopure functionalized oxocines; whereas the palladium‐catalyzed cyclizative coupling reaction of 2‐azetidinone‐tethered ε,ζ‐allendiols 4 furnished dioxonines 16 through a totally chemo‐ and regioselective 9‐endo oxycyclization. By contrast, the palladium‐catalyzed cyclizative coupling reaction of 2‐azetidinone‐tethered δ,ε‐allendiols 3 with aryl and alkenyl halides exclusively generated six‐membered‐ring compounds 14 a and 15 a . These results could be explained through a 6‐exo cyclization by chemo‐ and regiospecific attack of the secondary hydroxy group to the internal allene carbon. Chemo‐ and regiocontrol issues are mainly influenced by the length of the tether rather than by the nature of the metal catalysts and substituents. This reactivity can be rationalized by means of density functional theory calculations.     

Carbamoyl Radical‐Mediated Synthesis and Semipinacol Rearrangement of β‐Lactam Diols

In an approach to the biologically important 6‐azabicyclo[3.2.1]octane ring system, the scope of the tandem 4‐exo‐trig carbamoyl radical cyclization—dithiocarbamate group transfer reaction to ring‐fused β‐lactams is evaluated. β‐Lactams fused to five‐, six‐, and seven‐membered rings are prepared in good to excellent yield, and with moderate to complete control at the newly formed dithiocarbamate stereocentre. No cyclization is observed with an additional methyl substituent on the terminus of the double bond. Elimination of the dithiocarbamate group gives α,β‐ or β,γ‐unsaturated lactams depending on both the methodology employed (base‐mediated or thermal) and the nature of the carbocycle fused to the β‐lactam. Fused β‐lactam diols, obtained from catalytic OsO₄‐mediated dihydroxylation of α,β‐unsaturated β‐lactams, undergo semipinacol rearrangement via the corresponding cyclic sulfite or phosphorane to give keto‐bridged bicyclic amides by exclusive N‐acyl group migration. A monocyclic β‐lactam diol undergoes Appel reaction at a primary alcohol in preference to semipinacol rearrangement. Preliminary investigations into the chemo‐ and stereoselective manipulation of the two carbonyl groups present in a representative 7,8‐dioxo‐6‐azabicyclo[3.2.1]octane rearrangement product are also reported.     

The synthesis of metal–organic framework Al‐MIL‐53‐derived Brønsted acid catalyst and its application in the Mannich reaction

A metal–organic framework Al‐MIL‐53‐NH₂‐derived Brønsted acid catalyst (Al‐MIL‐53‐RSO₃H) has been synthesized employing a post‐synthetic modification strategy under mild conditions. The Al‐MIL‐53‐RSO₃H catalyst was successfully utilized in the nitro‐Mannich reaction taking advantage of its strong Brønsted acidity. Good to excellent yields of Mannich adducts were achieved for a variety of acylimine substrates in the presence of 0.1 mol% Al‐MIL‐53‐RSO₃H. Furthermore, the Al‐MIL‐53‐RSO₃H catalyst can be recycled five times without decreasing the yield and selectivity of Mannich adducts.     

Direct Catalytic Enantio‐ and Diastereoselective Mannich Reaction of Isocyanoacetates and Ketimines

A catalytic asymmetric synthesis of imidazolines with a fully substituted β‐carbon atom by a Mannich‐type addition/cyclization reaction of isocyanoacetate pronucleophiles and N‐diphenylphosphinoyl ketimines has been developed. When a combination of a cinchona‐derived aminophosphine precatalyst and silver oxide was employed as a binary catalyst system, good reactivity, high diastereoselectivities (up to 99:1 d.r.), and excellent enantioselectivities (up to 99 % ee) were obtained for a range of substrates.     

Direct Palladium‐Catalyzed β‐Arylation of Lactams

A direct and catalytic method is reported here for β‐arylation of N‐protected lactams with simple aryl iodides. The transformation is enabled by merging soft enolization of lactams, palladium‐catalyzed desaturation, Ar?X bond activation, and aryl conjugate addition. The reaction is operated under mild reaction conditions, is scalable, and is chemoselective. Application of this method to concise syntheses of pharmaceutically relevant compounds is demonstrated.