Cyclic Amidines Research Articles

Copper-Catalyzed Defluorinative [3 + 2] Cyclization of Amidines and Trifluoromethyl Carbenoids for the Synthesis of 5-Fluoroimidazoles.

A Cu-catalyzed [3 + 2] cyclization of amidines with trifluoromethyldiazo compounds is described. The reaction affords 5-fluoroimidazoles in good yields by cleaving dual C-F bonds in a CF3 group. Using 2-aminoazo heterocycles as the substrates, various annelated imidazoles containing a fluorine atom were also constructed by this method without changing the conditions. The resultant 5-fluoroimidazoles show high reactivity toward SNAr reactions with a series of nucleophiles.

BF3·OEt2-Mediated (3+2) Cycloaddition Reactions of Donor-Acceptor Cyclopropanes (DACs) with Cyanamides: Access to Cyclic Amidines

AbstractA BF3·OEt2-promoted facile synthesis of cyclic amidines (2-amino-1-pyrrolines) has been developed via the (3+2)-cycloaddition of cyanamides with donor-acceptor cyclopropanes (DACs). In addition to this, the protocol has been successfully extended to construct a dimerized amidine derivative and gram-scale synthesis with great efficiency.

Synthesis of Isoquinuclidines via Dearomative Diels-Alder Reaction of Cyclic Amidines with Indoles.

The development and utilization of new dienes and dienophiles for the controlled synthesis of isoquinuclidines is highly appealing. Herein, we describe a novel strategy for diastereoselective synthesis of indoline-fused isoquinuclidines via copper-catalyzed dearomative Diels-Alder reaction of cyclic amidines with indoles. This protocol avoids the use of unstable DHPs and activated alkenes, offering a more efficient and selective approach to synthesize isoquinuclidines.

Electrochemical Trifluoromethylation/Bicyclization of N-Cyanamide Alkenes: Synthesis of Bicyclic Amidine Derivatives.

An anodically oxidizing trifluoromethylation cascade of N-cyanamide alkene bearing two electronically differentiated olefin moieties was reported, in which various N-unsaturated acyl cyanamide alkenes and CF3SO2Na acting as readily available starting materials furnished nonaromatic fused azaheterobicyclic compounds in a highly efficient and sustainable manner. The broad substrate scope, facile scalability, and sustainability enabled this electrochemical process to be an appealing complement for trifluoromethylated cyclic amidines.

Sequential Nitrile Amidination-Reduction as a Straightforward Procedure to Selective Linear Polyamine Preparation.

A straightforward strategy toward the efficient synthesis of linear saturated polyamines containing 1,2-diaminoethane and/or 1,3-diaminopropane fragments has been developed. The procedure is based on the chemistry of 5- and 6-membered cyclic amidines, including their efficient synthesis from nitrile precursors and subsequent chemoselective reductive-opening by a borane-dimethyl sulfide complex. This two-step procedure provides a robust methodology for the synthesis of linear polyamine skeletons under nonharsh conditions and free of using selective protective groups or tedious workups.

Diastereoselective Synthesis of Fused Tricyclic Pyridopyrimidines via Tandem Cyclization of Allenoates and Cyclic Amidines.

The tandem cyclization of easily accessible allenoates and cyclic amidines for the synthesis of functionalized tricyclic pyridopyrimidines is reported herein. The annulation featured a broad substrate scope with good functional group tolerance under very mild conditions (35 examples, 32-85% yields). The pyridopyrimidines were obtained in a very short reaction time (1 min), at room temperature, under neat conditions, which offers an alternative way to the sustainable synthesis of functionalized pyridopyrimidines. The scalability of the developed protocol is further demonstrated by a gram-scale synthesis.

PhIO‐Mediated Cascade Reactions of Activated Acetylamides and Cyclic Amidines: Access to Polysubstituted Imidazolidin‐2‐ones

AbstractA facile and efficient synthesis of polysubstituted imidazolidin‐2‐ones has been developed via an oxidative cyclization reaction of activated acetyl amides and cyclic amidines mediated by iodosobenzene (PhIO). A mechanism is proposed for this transformation, which involves sequential intermolecular addition, Hofmann‐type rearrangement and intramolecular cyclization reactions. The novel protocol features readily available starting materials, mild reaction conditions, simple execution, metal‐free oxidative cyclization, and one‐pot procedure.

Stereodefined synthesis of cyclic amidines by domino 1,7-H shift and 6π electrocyclisation.

Unsaturated N2-sulfonyl amidines are transformed into valuable N-heterocyclic products when heated with BF2OTf. Mechanism studies suggest a domino 1,7-H shift, activating a C-H bond, followed by electrocylisation that results in stereodefined cyclic amidines.

Metal-free transfer hydrogenation/cycloaddition cascade of activated quinolines and isoquinolines with tosyl azides.

The difficulty in isolating cyclic enamines emanating from their intrinsic instability has impeded their exploration in cycloaddition reactions. Here, we achieved a metal-free domino reaction providing quinoline and isoquinoline-derived cyclic amidines by the cycloaddition of azides with in situ generated enamines via dearomatization.

Acyclic amidines in the Strecker-like Groebke-Blackburn-Bienayme’ (GBB) reaction

The Groebke-Blackburn-Bienayme’ Reaction (GBBR) is a well-established multi-component method to form imidazoles using cyclic amidines. In order to expand the scope of this reaction, we have explored the GBBR with acyclic amidines. We found that the acyclic amidine, benzamidine performed similarly to cyclic amidines with the electronics of the aldehyde having a significant influence on reaction yield. Other acyclic amidines including guanidine were less successful however the guanidine derivative, acetylguanidine showed promise. These findings suggest that acyclic amidines have the potential to be used to develop new imidazoles which can be further functionalized.

Electrochemical cyclization ofN-cyanamide alkenes with CF3SO2Na to access C,N-(bis)trifluoromethylated cyclic amidines and related compounds

An electrochemical trifluoromethylative cyclization ofN-cyanamide alkenes and alkynes is presented, which afforded (bis)-C,N-trifluoromethylated cyclic amidines, azines and amides with selective multiple bond formations in a controllable manner.

C-H Functionalization and C-N Bond Formation Approaches under Catalytic Conditions for the Synthesis of α-Ketoamides and 2,4-Disubstituted-1,3,5-triazines

This work describes an easy way to perform approach for the transformation of arylmethyl ketones to α-ketoamides using secondary amines as starting materials in the presence of iodine as a catalyst in water under peroxide free reaction conditions. The established amidation reaction proceeds via α-C(sp3)-H functionalization and C-N bond formation approaches in water at ambient temperature. On the other hand, a novel and straightforward synthesis of 2,4-disubstituted-1,3,5-triazines via nickel-catalyzed cyclization of amidines with DMSO as one-carbon synthon has been developed. The developed strategy proceeds via C-N bond formation.

Lanthanide-Catalyzed Tandem Addition of Amines to Cyanoalkenes: Synthesis of Cyclic Amidines.

A tandem insertion of aliphatic nitriles and unactivated alkenes to the N-H bond of secondary aliphatic amines catalyzed by simple trialkyl rare-earth metal complexes was disclosed. This reaction provides a highly atom-economic and stereoselective way to a range of cyclic amidines under mild reaction conditions.

Catalyst-Free [3 + 3] Annulation/Oxidation of Cyclic Amidines with Activated Olefins: When the Substrate Olefin Is Also an Oxidant.

Herein we describe a catalyst-free regioselective [3 + 3] annulation/oxidation reaction of cyclic amidines such as DBU (1,8-diazabicyclo(5.4.0)undec-7-ene) and DBN (1,5-diazabicyclo(4.3.0)non-5-ene) with activated olefins, i.e., 2-arylidenemalononitriles and 2-cyano-3-aryl acrylates, to afford tricyclic 2-pyridones and pyridin-2(1H)-imines, respectively. The mechanism has been proposed based on DFT calculations. In the reaction, the cyclic amidines serve as C,N-bisnucleophiles for the cyclization, while the olefins play a dual role by acting as both reactants and oxidants.

Electrochemical Synthesis of Benzimidazoles via Dehydrogenative Cyclization of Amidines.

The development of efficient and sustainable methodologies for the synthesis of N-heterocycles is a constant focus of organic synthesis. Herein an electrochemical method is reported for the synthesis of benzimidazoles through dehydrogenative cyclization of easily available N-aryl amidines. The reactions were conducted under simple constant current conditions in an undivided cell without need for catalysts, chemical oxidants, or additives, and produced H2 as the only theoretical byproduct.

Reversal of polarity by catalytic SET oxidation: synthesis of azabicyclo[m.n.0]alkanes via chemoselective reduction of amidines.

A one-pot catalytic method has been developed for the stereoselective synthesis of cyclopropane-fused cyclic amidines using CuBr2/K2S2O8 as an efficient single electron transfer (SET) oxidative system. The generality of this mild method is demonstrated with a wide variety of substrates to furnish pharmaceutically important amidines containing aza-bicyclic and novel aza-tricyclic frameworks in very good yields. A chemoselective reduction of cyclic amidines to 2-/3-azabicyclo[m.n.0]alkanes and octahydroindoles has been developed using a NaBH4/I2 reagent system. The synthetic scope of the chemoselective reduction of the amidine functionality has been exemplified in the stereoselective synthesis of an iminosugar based (±)-epiquinamide analogue.

Adrenergic Modulation With Photochromic Ligands

AbstractAdrenoceptors are ubiquitous and mediate important autonomic functions as well as modulating arousal, cognition, and pain on a central level. Understanding these physiological processes and their underlying neural circuits requires manipulating adrenergic neurotransmission with high spatio‐temporal precision. Here we present a first generation of photochromic ligands (adrenoswitches) obtained via azologization of a class of cyclic amidines related to the known ligand clonidine. Their pharmacology, photochromism, bioavailability, and lack of toxicity allow for broad biological applications, as demonstrated by controlling locomotion in zebrafish and pupillary responses in mice.

Adrenergic Modulation With Photochromic Ligands.

Adrenoceptors are ubiquitous and mediate important autonomic functions as well as modulating arousal, cognition, and pain on a central level. Understanding these physiological processes and their underlying neural circuits requires manipulating adrenergic neurotransmission with high spatio-temporal precision. Here we present a first generation of photochromic ligands (adrenoswitches) obtained via azologization of a class of cyclic amidines related to the known ligand clonidine. Their pharmacology, photochromism, bioavailability, and lack of toxicity allow for broad biological applications, as demonstrated by controlling locomotion in zebrafish and pupillary responses in mice.

Synthesis of Cyclic Amidines by Iridium-Catalyzed Deoxygenative Reduction of Lactams and Tandem Reaction with Sulfonyl Azides.

An efficient and convenient synthesis of various cyclic amidines has been achieved via iridium-catalyzed deoxygenative reduction of lactams with a silane followed by a one-pot cycloaddition reaction with sulfonyl azides. Using the novel tandem procedure, a large array of cyclic amidines bearing various sized rings were synthesized in good yields from readily available lactams. This methodology has been successfully utilized in the late stage diversification of complex architectures bearing a lactam moiety.

Utilization of Borane-Catalyzed Hydrosilylation as a Dearomatizing Tool: Six-Membered Cyclic Amidine Synthesis from Isoquinolines and Pyridines

AbstractIn this study, a convenient strategy to synthesize six-membered­ cyclic amidines from isoquinolines and pyridines has been developed. Borane-catalyzed hydrosilylation of each N-heteroarene was utilized as a dearomatizing tool. Substrate scope is broad with respect to both isoquinolines and pyridines, with various reaction pathways depending on the substitution pattern of the N-heteroarenes. The reaction mechanism and reactivity of each class of N-heteroarenes has been discussed. The resulting six-membered (Z)-sulfonyl amidine products are rarely reported and are mostly unprecedented. The scalability of this method and versatility of the cyclic amidine products are also presented.