A copper(II)‐catalyzed oxidative methylene‐bridged dimerization of two analogous imidazo[1,2‐a]pyridines has been achieved using N,N‐dimethylacetamide (DMA) as solvent cum methylene source. This reaction works with a variety of substituted imidazo[1,2‐a]pyridines giving their products in moderate to good yields. Isotopic labelling experiments revealed that the methylene group in the product originates from the N,N‐dimethyl moiety of DMA.
An efficient protocol has been developed for the methylenation of imidazo[1,2‐a]pyridines using dimethylacetamide (DMA) as methylene source in the presence of vanadyl acetylacetonate [VO(acac)2] as the catalyst and iodobenzene diacetate as the oxidant. The reaction involves coupling of sp3‐ and sp2‐hybridized carbons and proceeds through the formation of an iminium ion. A wide variety of imidazo[1,2‐a]pyridines were converted to bis(imidazo[1,2‐a]pyridin‐3‐yl)methanes in good to excellent yields. A gram‐scale reaction demonstrated the potential for the scale‐up processes.
A novel asymmetric [4+2] annulation of vinyl ketones with oxindole‐derived α,β‐unsaturated imines has been developed in the presence of a multifunctional thiourea‐phosphine catalyst derived from a natural amino acid, providing the first phosphine‐catalyzed enantioselective synthesis of 2′,3′‐dihydro‐1′H‐spiro[indoline‐3,4′‐pyridin]‐2‐ones in good yields with excellent stereoselectivities under mild conditions.
A wide range of imidazo[1,2‐a]pyridines are accessible from cheap and readily available 2‐aminopyridines and 1,3‐dicarbonyl compounds using a unique CBrCl3/2‐aminopyridine system for bromination at the α‐carbon. 2‐Aminopyridine is not only the substrate but also acts as a bromination shuttle, transferring the bromine atom from CBrCl3 to the α‐carbon of the 1,3‐dicarbonyl. The reaction mechanism involves a series of reversible steps, including an addition reaction with cyclic transition state, to form a bromo‐hemiaminal intermediate. Isolated yields of up to 97% were obtained under mild conditions and at short reaction times in this transition metal‐free, one‐pot synthesis.
A mild, catalytic, atom economical synthesis of imidazo[1,2‐a]pyridines has been developed: catalytic dichloro(2‐pyridinecarboxylato)gold [PicAuCl2] in the presence of an acid produces a range of imidazo[1,2‐a]pyridines in good yields starting from alkynes and 2‐aminopyridine N‐oxides. This strategy is mild and foreseen to be of particular use for the installation of stereogenic centers adjacent to the imidazo[1,2‐a]pyridine ring without loss of enantiomeric excess.
An efficient and practical copper‐catalyzed domino synthesis of benzo[4,5]imidazo[1,2‐a]pyrimidin‐4(10H)‐ones has been developed. The protocol uses N‐(2‐halophenyl)‐3‐alkylpropiolamides and cyanamide as the starting materials, inexpensive copper(I) iodide and pipecolinic acid as the catalyst and ligand, and the corresponding products were obtained in moderate to good yields.
Asymmetric allylation of (hetero)aromatic aldehydes by a zinc(II)‐allylbutyrolactone species catalyzed by a chiral BINOL‐type phosphoric acid gave β‐substituted α‐methylenebutyrolactones in 68 to >99% ee and 52–91% isolated yield. DFT studies on the intermediate Zn2+‐complex – crucial for chiral induction – suggest a six‐membered ring intermediate, which allows the phosphoric acid moiety to activate the aldehyde. The methodology was applied to the synthesis of the antitumour natural product (S)‐(−)‐hydroxymatairesinol.
By using Cinchona‐derived chiral phosphines as catalytic ligands, enantioenriched cis‐3a,8a‐hexahydropyrrolo[2,3‐b]indoles (ent‐HPIs), which are core scaffolds in a large array of biologically active natural products, can be convergently assembled under mild conditions through the silver(I)‐catalyzed asymmetric domino reaction of readily available isocyanoacetates and 2‐(2‐aminophenyl)acrylates. Various functionalities can be tolerated in the reaction, affording enantioenriched HPIs in high overall yields and good enantioselectivities (up to 92% ees).
The synthesis of novel planar heterocycles is at the heart of basic research as such scaffolds constitute key building blocks in important diverse areas of research: drug discovery, material sciences, and pesticides. The well‐known benzoxazole is often contained in drug candidates but tweaking its lipophilicity and target interaction points are often desired. In this respect, the oxazolo[4,5‐b]pyrazine is an attractive heterocyclic scaffold as it possesses increased water solubility as well as two additional hydrogen bonding acceptors. We here report a new Pd(II)‐catalyzed domino reaction comprising the first Pd(II)‐assisted intramolecular cyclization of an N‐(2‐chloro‐3‐heteroaryl)arylamide and validate its value by application to the first synthesis of 2‐substituted oxazolo[4,5‐b]pyrazines. We demonstrate that a bidentate phosphorus ligand as well as the presence of an aromatic nitrogen atom is required for the domino reaction to proceed. The robustness of the methodology is confirmed by the synthesis of 23 2‐substituted oxazolo[4,5‐b]pyrazine analogues in good‐to‐high yields and containing both electron‐withdrawing as well as electron‐donating substituents on the reacting arylamide.
An efficient copper‐catalyzed oxidative coupling of imidazo[1,2‐a]pyridines with methyl ketones to directly generate structurally sophisticated 1,2‐dicarbonyl imidazo[1,2‐a]pyridine derivatives under oxidative conditions is described. The reaction proceeds in good yields using the environmental friendly molecular oxygen as the oxidant. 18O‐Labelling experiments unambiguously established that the oxygen of the dicarbonyl products originated from oxygen rather than from water.
A convenient gold‐catalyzed strategy for the synthesis of imidazo[1,2‐a]pyridine derivatives has been developed via gold carbene complexes. This transformation opens a new synthetic route to a variety of 3‐carbonyl‐substituted imidazo[1,2‐a]pyridines using air as oxidant affording the products in good yields.
Treatment of cyclobutanecarboxamide with bis(trifluoroacetoxy)iodobenzene, PhI(OCOCF3)2, resulted in the formation of 1‐pyrroline via Hofmann rearrangement of the former followed by in situ ring expansion reaction of the cyclobutylamine intermediate. Further elaboration of this methodology to the synthesis of 2,3‐dihydro‐1H‐pyrrolo[2,1‐a]isoquinolinium salts has also been described.
The regioselectivity of the [3+2] cyclocondensation of trifluoromethyl‐α,β‐ynones with hydrazines can be readily tuned to preferentially afford either 3‐ or 5‐trifluoromethylpyrazoles through variation of the reaction conditions. Under catalysis with copper(II) acetate (2.0 mol%), cyclocondensation proceeded smoothly to yield 3‐trifluoromethylpyrazoles with high regioselectivity. In contrast, when the reaction was conducted in dimethyl sulfoxide under catalyst‐free conditions, the formation of 5‐trifluoromethylpyrazoles was predominantly observed.
An efficient synthetic strategy for the unique class of pyrazolo[1,2‐a]cinnolines was developed through a rhodium‐catalyzed oxidative coupling of N‐aryl‐1H‐pyrazol‐5(4H)‐ones with internal alkynes. This protocol features use of the pyrazolone function in the substrate as an intrinsic directing group, hexafluoroisopropyl alcohol (HFIP) as the solvent, and mild reaction conditions as well as a wide substrate scope.
A new enantioselective route to spiro[piperidine‐3,3′‐oxindoles] from isatin ketimines is described. The aza‐Henry reaction of N‐Boc‐isatin ketimines with methyl 4‐nitrobutyrate in the presence of a Ph2BOX‐CuBr2 complex provided the corresponding nitro amino esters with good diastereoselectivity and excellent enantioselectivity (up to >99% ee). The aza‐Henry adducts were transformed into spiro[piperidine‐3,3′‐oxindoles] after reduction of the nitro group to oxime, and cleavage of the N‐Boc group and lactamisation.
An unprecedented organocatalytic enantioselective cascade Michael/hemiketalization/retro‐aldol reaction of 2‐[(E)‐2‐nitrovinyl]phenols and 2,4‐dioxo‐4‐arylbutanoates is described. With a bifunctional squaramide catalyst incorporating (1R,2R)‐1,2‐diphenylethane‐1,2‐diamine, the reactions afford products in 75–99% yields with 80–98% ee. This process provides an enantioselective pathway for the synthesis of chiral α‐keto esters, precursors of 3‐arylproline derivatives, δ‐amino α‐keto acids or cyclic α‐keto lactams.
A novel synthetic method to access fused indolin‐3‐ones with a tetrasubstituted carbon stereocenter has been developed via NHC‐catalyzed umpolung formal [3+3] cycloaddtion of enals with isatogens. This methodology could be also applied for the quick construction of the 6‐5‐5 tricyclic pyrrolo[1,2‐a]indole skeleton which is frequently found as a core structure of many indole alkaloids.
The highly catalytic asymmetric α‐hydroxylation of β‐indanone esters and β‐indanone amides using peroxide as the oxidant was realized with a new C‐2′ substituted Cinchona alkaloid derivatives. The two enantiomers of α‐hydroxy‐β‐indanone esters could be obtained by simply changing the oxidant. This protocol allows a convenient access to the corresponding α‐hydroxy‐β‐indanone esters and α‐hydroxy‐β‐indanone amides with up to 99% yield and 98% ee.
An efficient synthesis of (E)‐5‐aryl(halo)methylenebicyclo[2.2.2]oct‐2‐enes is reported. Lewis acid‐promoted carbohalogenation of 4‐(3‐arylprop‐2‐ynyl)‐cyclohex‐2‐enols in dichloromethane proceeds rapidly to afford the exo‐methylene‐bridged bicycles in good yields. This method also provides an easy access to (E)‐5‐aryl(halo)methylenebicyclo[2.2.1]hept‐2‐enes from the five‐membered ring 2,6‐enynols. The reactions are procedurally simple and high yielding, producing the aryl(halo)methylene‐bridged bicycles in minutes under air and mild conditions.
Silver‐catalyzed three‐component, tandem reactions of 4‐alkynyl‐2‐oxo‐2H‐chromene‐3‐carbaldehydes, amines and various nucleophiles result in the formation of highly functionalized chromeno[3,4‐c]pyridin‐5‐ones in high yields. Gold‐catalyzed [4+2] cycloadditions of 4‐alkynyl‐2‐oxo‐2H‐chromene‐3‐carbaldehydes with alkynes or alkenes have also been achieved to afford benzo[c]chromen‐6‐ones efficiently.
