Intermolecular Annulation Research Articles

Synthesis of Unprotected and Highly Substituted Indoles by the Ruthenium(II)-Catalyzed Reaction of Phenyl Isocyanates with Diaryl/Diheteroaryl Alkynes/Ethyl-3-phenyl Propiolates.

A one-pot transformation has been developed for the synthesis of unprotected and highly substituted indoles by an in situ installed carbamide-directed Ru(II)-catalyzed intermolecular oxidative annulation of phenyl isocyanates with diaryl/diheteroaryl alkynes/ethyl phenyl propiolates in the presence of Cu(OAc)2·H2O as an oxidant and AgSbF6 as an additive at 120 °C within 3 h.

Recent Advances in Construction of Polycyclic Natural Product Scaffolds via One-Pot Reactions Involving Alkyne Annulation

Polycyclic scaffolds are omnipresent in natural products and drugs, and the synthetic strategies and methods toward construction of these scaffolds are of particular importance. Compared to simple cyclic ring systems, polycyclic scaffolds have higher structure complexity and diversity, making them suitable for charting broader chemical space, yet bringing challenges for the syntheses. In this review, we surveyed progress in the past decade on synthetic methods for polycyclic natural product scaffolds, in which the key steps are one-pot reactions involving intermolecular or intramolecular alkyne annulation. Synthetic strategies of selected polycyclic carbocycles and heterocycles with at least three fused, bridged, or spiro rings are discussed with emphasis on the synthetic efficiency and product diversity. Recent examples containing newly developed synthetic concepts or toolkits such as collective and divergent total synthesis, gold catalysis, C–H functionalization, and dearomative cyclization are highlighted. Finally, several “privileged synthetic strategies” for “privileged polycyclic scaffolds” are summarized, with discussion of remained challenges and future perspectives.

Transition Metal-Catalyzed Intermolecular Cascade C-H Activation/Annulation Processes for the Synthesis of Polycycles.

Polycycles are abundantly present in numerous advanced chemicals, functional materials, bioactive molecules and natural products. However, the strategies for the synthesis of polycycles are limited to classical reactions and transition metal-catalyzed cross-coupling reactions, requiring pre-functionalized starting materials and lengthy synthetic operations. The emergence of novel approaches shows great promise for the fields of organic/medicinal/materials chemistry. Among them, transition metal-catalyzed C-H activation followed by intermolecular annulation reactions prevail, due to their straightforward manner with high atom- and step-economy, providing rapid, concise and efficient methods for the construction of diverse polycycles. Several strategies have been developed for the synthesis of polycycles, relying on sequential multiple C-H activation/annulation, or combination of C-H activation/annulation and further interaction with a proximal group, or merger of C-H activation with a cycloaddition reaction, or in situ formation of the directing group. These are attractive, efficient, step- and atom-economic methods starting from commercially available materials. This Minireview will provide an introduction to transition metal-catalyzed C-H activation for the synthesis of polycycles, helping researchers to discover indirect connections and reveal hidden opportunities. It will also promote the discovery of novel synthetic strategies relying on C-H activation.

Electrochemically Enabled Intramolecular and Intermolecular Annulations of Alkynes

AbstractElectrosynthesis is recognized as one of the most powerful and sustainable methods in organic chemistry. Recently, electrochemically enabled annulations of carbon‐carbon triple bonds have been successfully achieved, and have broadened prospects for the application of the emerging method with cyclization of alkynes. Thus, herein we outline the recent progress made on electrochemically enabled annulations of alkynes. In addition, an emphasis on the scope, limitations and the mechanisms of these reactions is made in this review.magnified image

Copper(II)-catalyzed decarboxylative cyclization for accessing biologically relevant 3-(2-furanyl) Indoles via 3-cyanoacetyl indoles and cinnamic acids

A novel and efficient route for the synthesis of 3-(2-furanyl) indoles from the readily available 3-cyanoacetyl indoles and α,β-unsaturated carboxylic acids via Cu(II)-catalyzed decarboxylative, intermolecular annulation is reported. In this transformation, di-tert-butyl peroxide was used as an external oxidant. This reaction undergoes radical addition, decarboxylative processes, and provides a facile regioselective 3-(2-furanyl) indole derivatives in good to excellent yields.

Sulfenyl Ynamides in Gold Catalysis: Synthesis of Oxo‐functionalised 4‐aminoimidazolyl Fused Compounds by Intermolecular Annulation Reactions

AbstractFunctionalised N‐heterocyclic pyridinium N‐aminides have been designed and synthesised to evaluate a nitrenoid‐based annulation strategy into imidazole‐fused oxo‐substituted frameworks of importance to medicinal and agrochemical discovery programmes. Sulfenyl substituted ynamides were identified as privileged reactants affording productive gold‐catalysed annulation reactions with these and other nitrenoids. This annulation method provides selective and efficient access into geminally amino‐sulfenyl substituted nitrogen heterocycles under mild reaction conditions.magnified image

Palladium‐Catalyzed Intermolecular Carbopalladation Cascade: Facile Synthesis of [1,2,3]Triazolo[1,5‐a]quinolines from o‐Triazole Bromobenzenes and Internal Alkynes

AbstractA palladium‐catalyzed intermolecular annulation and arylation cascade between internal alkynes and o‐triazole bromobenzenes was developed, delivering to various polysubstituted [1,2,3]triazolo[1,5‐a]quinolines. Broad substrate scope, great functional group tolerance and simple operation of this transformation, hold great synthetic potential for the rapid construction of fused N‐heterocycles with biologically activity.

Aryne-Induced SNAr/Dearylation Strategy for the Synthesis of Fluorinated Dibenzophospholes from Triarylphosphines via a P(V) Intermediate.

We report on a method for the synthesis of fluorinated dibenzophospholes using triarylphosphine via dearylative annulation with an aryne. This intermolecular annulation allows the preparation of a variety of fluorinated dibenzophospholes from simple building blocks. The key to the success of this dearylative annulation is the formation of a five-coordinated tetraarylfluorophosphorane. In this work, we successfully synthesized stable tetraarylfluorophosphorane, the structure of which was unambiguously determined by X-ray crystallography.

Phenanthrenes/dihydrophenanthrenes: the selectivity controlled by different benzynes and allenes.

A method for the intermolecular annulation of benzynes with allenes is disclosed. This protocol utilized allenes as an unconventional diene component for the selective synthesis of phenanthrenes and dihydrophenanthrenes under the control of different benzyne precursors, featuring high atom-economy and good functional group compatibility. Density functional theory (DFT) calculations reveal that different migratory routes of the aromatic C-H bond are crucial for the observed selectivity.

Electrochemical Synthesis of 1-Naphthols by Intermolecular Annulation of Alkynes with 1,3-Dicarbonyl Compounds.

C-centered radical cyclization under electrochemical conditions is a feasible strategy for constructing cyclic structures. Reported herein is the electrochemical synthesis of highly functionalized 1-naphthols using alkynes and 1,3-dicarbonyl compounds by (4 + 2) annulation of C-centered radical. Electrolysis was conducted with Cp2Fe as redox catalyst, thereby eliminating the use of oxidants and transition-metal catalysts. The synthesized 1-naphthol compounds showed good antitumor activity in vitro, and further studies indicated that compound 3bl induced tumor cell apoptosis.

Gram-Scale Synthesis of 3-Sulfonyl Flavanones.

In this paper, an easy-operational, high-yielding method for the gram-scale synthesis of 3-sulfonyl flavanones is described by a one-pot straightforward POCl3 mediated intermolecular (5 + 1) annulation of the β-ketosulfones with an o-hydroxyaryl group (dual nucleophile) and arylaldehydes (dual electrophile) in refluxing toluene for 3 h. A plausible mechanism is proposed and discussed. This protocol provides a highly effective annulation via one carbon-oxygen (C-O) and one carbon-carbon (C-C) bond formations.

Synthesis of Isoxazolines and Oxazines by Electrochemical Intermolecular [2 + 1 + n] Annulation: Diazo Compounds Act as Radical Acceptors.

Reported herein is an unprecedented synthesis of isoxazolines and oxazines through electrochemical intermolecular annulation of alkenes with tert-butyl nitrite, in which diazo compounds serve as radical acceptors. Notably, [2 + 1 + 2] and [2 + 1 + 3] annulations occur when styrenes and allylbenzenes are used as substrates, respectively. The latter reaction undergoes group migration to form more stable radical, manifesting radical route instead of conventional 1,3-dipolar cycloaddition occurs. Moreover, scale-up experiments suggest the potential application value of these transformations in industry.

Expeditious Access to Functionalized Tricyclic Pyrrolo-Pyridones via Tandem or Sequential C-N/C-C Bond Formations.

The facile synthesis of both saturated and unsaturated tricyclic pyrrolo-pyridones starting from a single readily available, common monocyclic reagent has been developed. An intermolecular annulation via a tandem Buchwald-Hartwig/Heck reaction led to the synthesis of β-carbolinones. The analogous semisaturated tricyclic pyrrolo-pyridones were prepared in good to excellent yields by sequential Buchwald-Hartwig and Fischer indole reactions. The methods feature mild reaction conditions and good functional group tolerance.

Combining the Ugi-azide multicomponent reaction and rhodium(III)-catalyzed annulation for the synthesis of tetrazole-isoquinolone/pyridone hybrids.

An efficient sequence based on the Ugi-azide reaction and rhodium(III)-catalyzed intermolecular annulation has been established for the preparation of tetrazole-isoquinolone/pyridone hybrids. Several N-acylaminomethyltetrazoles were reacted with arylacetylenes to form the hybrid products in moderate to very good yields. The method relies on the capacity of the rhodium catalyst to promote C(sp2)–H activation in the presence of a suitable directing group. The Ugi-azide reaction provides broad molecular diversity and enables the introduction of the tetrazole moiety, which may further assist the catalytic reaction by coordinating the metal center. The scope of the isoquinolones is very wide and may be extended to the preparation of complex compounds having heterocyclic moieties such as pyridone, furan, thiophene and pyrrole, as well as the corresponding benzo-fused derivatives. The developed procedure is simple, reproducible and does not require inert conditions.

Trifluoroacetic Anhydride Mediated One-Pot Synthesis of 1-Aryl Isochroman-3-ones via the Carboxy-Pictet–Spengler Reaction

In this paper, a novel and open-vessel route for the facile-operational synthesis of 1-aryl isochroman-3-ones is described via (CF3CO)2O (trifluoroacetic anhydride, TFAA)-mediated intermolecular (4 + 2) annulation of oxygenated arylacetic acids with arylaldehydes or ketones under mild reaction conditions. A plausible mechanism is proposed and discussed herein. Various reaction conditions are investigated for efficient transformation under an environmentally friendly one-pot carboxy-Pictet-Spengler reaction.

N-Heterocyclic Carbene Catalyzed (5+1) Annulations Exploiting a Vinyl Dianion Synthon Strategy.

Direct polarity inversion of conjugate acceptors provides a valuable entry to homoenolates. N-heterocyclic carbene (NHC) catalyzed reactions, in which β-unsubstituted conjugate acceptors undergo homoenolate formation and C-C bond formation twice, have been developed. Specifically, the all-carbon (5+1) annulations give a range of mono- and bicyclic cyclohexanones (31 examples). In the first family of annulations, β-unsubstituted acrylates tethered to a divinyl ketone undergo cycloisomerization, providing hexahydroindenes and tetralins. In the second, partially untethered substrates undergo an intermolecular (5+1) annulation involving dimerization followed by cycloisomerization. While enantioselectivity was not possible with the former, the latter proved viable, allowing cyclohexanones to be produced with high levels of enantiopurity (most >95:5 e.r.) and exclusive diastereoselectivity (>20:1 d.r.). Derivatizations and mechanistic studies are also reported.

N‐Heterocyclic Carbene Catalyzed (5+1) Annulations Exploiting a Vinyl Dianion Synthon Strategy

AbstractDirect polarity inversion of conjugate acceptors provides a valuable entry to homoenolates. N‐heterocyclic carbene (NHC) catalyzed reactions, in which β‐unsubstituted conjugate acceptors undergo homoenolate formation and C−C bond formation twice, have been developed. Specifically, the all‐carbon (5+1) annulations give a range of mono‐ and bicyclic cyclohexanones (31 examples). In the first family of annulations, β‐unsubstituted acrylates tethered to a divinyl ketone undergo cycloisomerization, providing hexahydroindenes and tetralins. In the second, partially untethered substrates undergo an intermolecular (5+1) annulation involving dimerization followed by cycloisomerization. While enantioselectivity was not possible with the former, the latter proved viable, allowing cyclohexanones to be produced with high levels of enantiopurity (most >95:5 e.r.) and exclusive diastereoselectivity (>20:1 d.r.). Derivatizations and mechanistic studies are also reported.

Iron(II)‐Based Metalloradical Activation: Switch from Traditional Click Chemistry to Denitrogenative Annulation

AbstractA unique concept for the intermolecular denitrogenative annulation of 1,2,3,4‐tetrazoles and alkynes was discovered by using a catalytic amount of Fe(TPP)Cl and Zn dust. The reaction precludes the traditional, more favored click reaction between an organic azide and alkynes, and instead proceeds by an unprecedented metalloradical activation. The method is anticipated to advance access to the construction of important basic nitrogen heterocycles, which will in turn enable discoveries of new drug candidates.

Iron(II)-Based Metalloradical Activation: Switch from Traditional Click Chemistry to Denitrogenative Annulation.

A unique concept for the intermolecular denitrogenative annulation of 1,2,3,4-tetrazoles and alkynes was discovered by using a catalytic amount of Fe(TPP)Cl and Zn dust. The reaction precludes the traditional, more favored click reaction between an organic azide and alkynes, and instead proceeds by an unprecedented metalloradical activation. The method is anticipated to advance access to the construction of important basic nitrogen heterocycles, which will in turn enable discoveries of new drug candidates.

Phosphine‐Catalyzed Intermolecular Annulations of Fluorinated ortho‐Aminophenones with Alkynones – The Switchable [4+2] or [4+2]/[3+2] Cycloaddition

AbstractA phosphine‐catalyzed intermolecular annulation reaction of functionalized ortho‐aminoacetophenones with alkynones has been disclosed in this paper. A variety of 2‐alkynylquinolines and benzo‐fused indolizine were selectively afforded in moderate to good yields at different reaction temperatures and with different phosphine catalysts via the in situ generated zwitterionic intermediate derived from alkynone and phosphine.magnified image