A new postcondensation multicomponent reaction (MCR) methodology, comprising oxidative deaminations enabling access to multiple privileged carbonyl-containing scaffolds in two steps, is described. These protocols allow facile access to functionalized α-ketoamide and α-ketotetrazole small-molecule peptidomimetic-like building blocks from prototypical synthons with two points of diversity. Incorporation of chalcone and alkynyl moieties with further ring-forming reactions enables access to additional novel heterocyclic ring systems, including a unique and potentially highly pharmacologically relevant scaffold, a 1,2-selenazol-3(2H)-one.

A concise one-pot three-component reaction that affords fluorescent indolizines, benzo[d]pyrrolo[2,1-b]thiazoles, and pyrrolo[1,2-a]pyrazines is reported. The methodology involves the formation of a heterocyclic 1-aza-1,3-diene derived from a Knoevenagel condensation between an aldehyde and 2-methyl-ene-cyano aza-heterocycles, followed by [4 + 1] cycloaddition of acetyl cyanide behaving as a non-classical isocyanide replacement.

Herein, a two-step MCR-oxidation methodology accessing decorated 2° α-ketoamides and α-ketotetrazoles is described via a catalytic copper(I)-mediated C–N oxidation/acidic hydrolysis of Ugi-three-component and Ugi-azide reaction products. The ability to install diversity from aldehyde and isocyanide synthons allows rapid complexity generation. Of note, (1) 2° α-ketoamides are traditionally difficult to access and more so reminiscent of the endogenous peptide bonds. (2) The route to α-keto-tetrazoles is significantly shorter than that in previous reports.

Two-step methodology described herein showcases the first example of an oxidation/oxidative amidation cyclization cascade of MCR products toward diverse N-functionalized isatins. Products of both the Ugi 3CR and the Ugi azide reactions are oxidatively cyclized through a postcondensation process utilizing selenium dioxide. This methodology was found to be applicable for the generation of bis-peptidomimetic-like isatins containing multiple points of diversification.

A cesium carbonate promoted three-component reaction of N–H containing heterocycles, primary or secondary amines, arylglyoxaldehydes, and anilines is reported. The key step involves a tandem sequence of N-1 addition of a heterocycle or an amine to preformed α-iminoketones, followed by an air- or oxygen-mediated oxidation to form α-oxo-acetamidines. The scope of the reaction is enticingly broad, and this novel methodology is applied toward the synthesis of various polycyclic heterocycles.

A concise one-pot 3-step cascade reaction to biologically significant imidazo[1,2-a]heterocycles is described. The methodology utilizes acetyl cyanide as a non-classical isocyanide replacement for TMSCN in a microwave-assisted [4+1] cycloaddition (the Groebke–Bienaymé–Blackburn reaction) followed by a Strecker reaction under catalysis free conditions. The methodology proceeds with operational simplicity, short reaction times, and high bond forming efficiency.

This Letter describes novel methodology for the rapid assembly of unprecedented and likely biologically relevant imidazo-tetrazolodiazepinones. The product of a TMSN3-Ugi multi-component reaction is treated with an excess of isocyanate to generate 1,5-disubstituted tetrazolo-hydantoins functionalized with an internal-masked amino nucleophile previously introduced by the isocyanide input. Final products are obtained in good overall yields after microwave irradiation of the tetrazolo-hydantoin in acidic media. This methodology allows the production of complex polycyclic compounds in a mere three synthetic steps.

Highlights•A relativistic two-component theoretical of organo-cesium (lanthanide and actinide) is presented.•Energy decomposition analysis evidences an ionic character on the ligand–metal interaction in organo-cesium compounds.•The substitution of Cs+ ions by the isoelectronic La3+ and Th4+ produce an increment of the covalency on the studied compound.•The increment of the covalency previously reported suggests the viability of obtain organo-lanthanide/actinide by Ugi-type of synthesis.Relativistic DFT calculations suggest that two organo-cesium complexes studied herein afford large HOMO–LUMO gaps of around 2.4 eV with the PBE xc-functional, which accounts for their stability. Energy decomposition studies suggest these two complexes are largely ionic with about 20% covalency. However, when the Cs+ ions are substituted by the isoelectronic La3+ and Th4+, their predicted ionicity decreases significantly. The significant increase in covalence indicates that employing Ugi reaction cascades that afford tetramic acid-based organo-cesium complexes may be extended to La3+ and Th4+ organometallics.Graphical abstract

Several novel cascade reactions are herein reported that enable access to a variety of unique mono- and bis-heterocyclic scaffolds. The sequence of cascade events are mediated through acid treatment of an Ugi adduct that affords 1,5-benzodiazepines which subsequently undergo an elegant rearrangement to deliver (E)-benzimidazolones, which through acid-promoted tautomerization convert to their corresponding (Z)-isomers. Moreover, a variety of heterocycles tethered to (Z)-benzimidazole-2-ones are also accessible through similar domino-like processes, demonstrating a general strategy to access significantly new scaffold diversity, each containing four points of potential diversification. Final structures of five scaffolds have been definitively proven by X-ray crystallography.

This Letter reveals a unique, user-friendly, concise two-step, one-pot protocol for the synthesis of highly substituted quinoxalines. Conducting the Ugi reaction with appropriately functionalized classical Ugi reagents with subsequent acid treatment of the Ugi adduct affords collections of diversified quinoxalines in good to excellent yields. The methodology exploits what may be viewed as a ‘convertible carboxylic acid’, which in addition may be captured in an intramolecular sense to generate structurally complex 2-benzimidazolylquinoxalines in a mere two steps.

An isocyanide-based multicomponent reaction (IMCR) utilized for the rapid assembly of novel, biologically relevant dihydropyrrolo[1,2-a]quinoxalines-amidines is herein presented. Starting from 1-(2-aminophenyl)pyrroles, aldehydes, and isonitriles, the target heterocyclic scaffold is assembled in a one-pot, operationally friendly process. With three points of diversity and formation of three chemical bonds in one step, this strategy proves to be very general. Novel, mild methodology for the generation of amidines from secondary amine anilines and isonitriles is also introduced.Graphical abstract

Five elegant and switchable three-component reactions which enable access to a new series of nitrogen-containing heterocycles are reported. A novel one-step addition of an isocyanide to a hydrazine derived Schiff base affords unique six-membered pyridotriazine scaffolds (A and E). With slight modification of reaction conditions and replacement of the nucleophilic isocyanide moiety with different electrophiles (i.e., isocyanates, isothiocyanates, cyclic anhydrides, and acyl chlorides) five-membered triazolopyridine scaffolds (B, D, F, G) are generated in a single step. Furthermore, the use of phenyl hydrazine enables access to dihydroindazole-carboxamides, devoid of a bridge-head nitrogen (C). All protocols are robust and tolerate a diverse collection of reactants, and as such, it is expected that the new scaffolds and associated chemistry will garner high interest from medicinal chemists involved in either file enhancement or specific target-related drug discovery campaigns.

The aldol reaction has been evaluated in combination with the Ugi multicomponent reaction to assemble richly decorated mono- and polycyclic systems via expeditious cascade pathways. A small collection of pyrrolinones was generated thereof, and the scarcely accessible pyridoquinoxalinedione scaffold was also prepared by designing an additional nucleophilic substitution step in this domino sequence requiring minimal operational effort.

1,5-Disubstituted tetrazoles are an important drug-like scaffold known for their ability to mimic the cis-amide bond conformation. The scaffold is readily accessible via substitution of the carboxylic acid component of the Ugi multi-component reaction (MCR) with TMSN3 in what is herein denoted the Ugi-azide reaction. This full paper presents a concise, novel, general strategy to access a plethora of new heterocylic scaffolds utilizing tethered aldo/keto-acids/esters in the Ugi-azide reaction followed by a ring closing event that generates novel highly complex bis-heterocyclic lactam-tetrazoles.

Dihydropyrazino-quinazolinedione chemotypes are complex and structurally challenging structures of biological interest, being found in the marine alkaloids such as brevianamide M–N and fumiquinazolines A–C. Herein we report the synthesis of this tricyclic system in three synthetic operations by means of an Ugi multi-component reaction (MCR) followed by a tandem N-acyliminium ion cyclization-intramolecular nucleophilic addition reaction sequence. Additional structural diversification for further library enrichment was also accomplished via sequential N-alkylation and N-acylation/sulfonation.Herein, we report the production of a diversified tricyclic scaffold in 3 synthetic operations involving an Ugi multicomponent reaction followed by an N-acyliminium ion cyclization cascade. Further functionalization of the biologically appealing tricyclic core 24 was achieved via sequential N-alkylation and N-acylation and/or sulfonation.

A straightforward procedure for the preparation of N-quinoxaline-indoles is presented. A base-catalyzed one-pot addition of indoles to a preformed α-iminoketone proceeds on the N-1 indole and the subsequent adduct undergoes an acid-mediated deprotection of an internal amino nucleophile, intramolecular cyclization, and final oxidation generating N-1-quinoxaline-indoles in good yield.A novel route to N-1-quinoxaline-indoles is presented. Base-catalyzed addition of indole to preformed α-iminoketones proceeds at the N-1 indole position and the subsequent adduct undergoes an acid-mediated Boc-deprotection, cyclization, and oxidation generating N-1-quinoxaline-indoles in good yield in a succinct three steps.

This Letter reports the synthesis and biological evaluation of a collection of aminophthalazines as a novel class of compounds capable of reducing production of PGE2 in HCA-7 human adenocarcinoma cells. A total of 28 analogs were synthesized, assayed for PGE2 reduction, and selected active compounds were evaluated for inhibitory activity against COX-2 in a cell free assay. Compound 2xxiv (R1 = H, R2 = p-CH3O) exhibited the most potent activity in cells (EC50 = 0.02 μM) and minimal inhibition of COX-2 activity (3% at 5 μM). Furthermore, the anti-tumor activity of analog 2vii was analyzed in xenograft mouse models exhibiting good anti-cancer activity.This Letter describes the synthesis and biological evaluation of a collection of aminophthalazines capable of reducing PGE2 production in HCA-7 colon cancer cells. A total of twenty eight analogs were tested and active compounds were identified. Furthermore, the anti-tumor activity of analog 2vii was analyzed in xenograft mouse models demonstrating promising anti-cancer activity.

An efficient multicomponent-based methodology providing a new entry into a medicinally important complex heterocyclic core is presented. The strategy is very general and able to endow target compounds with the highest possible number of diversity points. Notably, four new chemical bonds and two aromatic rings are formed in a one-pot fashion.

With 24.3 million people affected in 2005 and an estimated rise to 42.3 million in 2020, dementia is currently a leading unmet medical need and costly burden on public health. Seventy percent of these cases have been attributed to Alzheimer’s disease (AD), a neurodegenerative pathology whose most evident symptom is a progressive decline in cognitive functions. Dual specificity tyrosine phosphorylation regulated kinase-1A (DYRK1A) is important in neuronal development and plays a variety of functional roles within the adult central nervous system. The DYRK1A gene is located within the Down syndrome critical region (DSCR) on human chromosome 21 and current research suggests that overexpression of DYRK1A may be a significant factor leading to cognitive deficits in people with Alzheimer’s disease (AD) and Down syndrome (DS). Currently, treatment options for cognitive deficiencies associated with Down syndrome, as well as Alzheimer’s disease, are extremely limited and represent a major unmet therapeutic need. Small molecule inhibition of DYRK1A activity in the brain may provide an avenue for pharmaceutical intervention of mental impairment associated with AD and other neurodegenerative diseases. We herein review the current state of the art in the development of DYRK1A inhibitors.Keywords: Alzheimer’s disease; Down syndrome; DYRK1A; DYRK1A inhibitors

An Ugi one-pot three-component four-center reaction was coupled with a subsequent acid mediated cyclodehydration step to furnish a multitude of unique scaffolds having in common an embedded or attached benzimidazole and often a ring system formed through lactamization. Using combinations of tethered Ugi inputs typically via tethered acid-ketone inputs and supporting reagents containing masked internal nucleophiles, such scaffolds were produced in good to excellent yields in an operationally friendly manner.Keywords: benzimidazole; lactams; one-pot; postcondensation; Ugi reaction

A one-pot, two-step synthesis of bis-pyrrolidinone tetrazoles has been established via the Ugi–Azide reaction using methyl levulinate, primary amines, isocyanides and azidotrimethylsilane with subsequent acid treatment to catalyze the lactam formation. The efficiency of the protocol was established followed by a successful transition to library production in four 24-well plates.Keywords: 1,5-disubstituted tetrazoles; Ugi reaction

This Letter discloses a novel concise synthesis of a series of 2,4,5-trisubstituted oxazoles via a tandem Ugi/Robinson–Gabriel sequence. Herein, 2,4-dimethoxybenzylamine 1 was used as an ammonia equivalent in combination with arylglyoxal 3 and supporting Ugi reagents, an isonitrile and carboxylic acid. As such the product of the acid treated Ugi intermediate is ideally configured to undergo a Robinson–Gabriel cyclodehydration reaction to yield the desired oxazole scaffold 5.A novel concise synthesis of a series of 2,4,5-trisubstituted oxazoles 5 via a tandem Ugi/Robinson–Gabriel sequence is reported.

This Letter presents a novel three step solution phase protocol to synthesize 3-(tetrazol-5-yl)quinoxalin-2(1H)-ones. The strategy utilizes ethyl glyoxalate and mono-N-Boc-protected-o-phenylenediamine derivatives in the Ugi-Azide multi-component reaction (MCR) to generate a unique 1,5-disubstituted tetrazole. Subsequent acid treatment stimulates a simultaneous Boc deprotection and intramolecular cyclization leading to bis-3,4-dihydroquinoxalinone tetrazoles. Direct oxidation using a stable solid-phase radical catalyst (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) with ceric ammonium nitrate (CAN) in catalytic fashion initiating aerobic oxidation, completes the entire procedure to generate a series of original unique bis-quinoxalinone tetrazoles. The method was also expanded to produce a bis-benzodiazepine tetrazole.This Letter describes a novel three step solution phase protocol to synthesize 3-(tetrazol-5-yl)quinoxalin-2(1H)-ones that utilizes the Ugi-Azide MCR followed by cyclization under acidic condition and immediate oxidation with TEMPO/CAN. The method was also expanded to produce a bis-benzodiazepine tetrazole.

A facile and expeditious synthetic approach for the synthesis of α-ketoamides 3 is described. A series of α-ketoamides 3 was synthesized via reaction of selenium dioxide-mediated oxidative amidation between arylglyoxals 1 and secondary amines 2, and accelerated with microwave irradiation. Our findings indicate that constrained amines, such as piperazine and piperidine exhibit higher conversions for this transformation. This reaction was explored by synthesizing a series of α-ketoamides 3 from various arylglyoxals 1 with cyclic and acyclic secondary amines 2.A facile and expeditious approach for the synthesis of α-ketoamides is described. A series of α-ketoamides 3 was synthesized via reaction of a SeO2 mediated oxidative amidation between arylglyoxals 1 and secondary amines 2, and accelerated with microwave irradiation. Our findings indicate that constrained amines such as piperazine and piperidine exhibit higher conversions for this transformation. This reaction was explored by synthesizing a series of α-ketoamides 3 from various arylglyoxals 1 with cyclic and acyclic secondary amines 2.

The following report describes novel methodology for the rapid synthesis of unique conformationally constrained norstatine analogs of potential biological relevance. A PADAM (Passerini reaction–Amine Deprotection–Acyl Migration reaction) sequence is followed by a TFA-mediated microwave-assisted cyclization to generate the final benzimidazole isostere of the norstatine scaffold in moderate to good yields. The applicability of this solution phase methodology to the preparation of a small collection of compounds is discussed.The following report describes novel methodology for the rapid synthesis of unique conformationally constrained norstatine analogs of potential biological relevance. A PADAM (Passerini reaction–Amine Deprotection–Acyl Migration reaction) sequence is followed by a TFA-mediated microwave-assisted cyclization to generate the final benzimidazole isostere of the norstatine scaffold in good yields. The applicability of this solution phase methodology to the preparation of a small collection of compounds is discussed.

This Letter describes novel methodology for the rapid assembly of new and biologically appealing 1,5-substituted tetrazole-hydantoins and thiohydantoins. The product of a TMSN3-Ugi multi-component reaction is treated with an excess of isocyanate or isothiocyanate to generate the final scaffold in moderate to good yields. The applicability of this solution phase methodology to the preparation of a small collection of compounds is discussed.

A concise synthesis of two pharmacologically relevant classes of molecules possessing the imidazoquinoxaline core is reported. The protocol involves use of 1,2-phenylenediamines and glyoxylic acid derivatives, namely ethyl glyoxylate or benzylglyoxamide, along with tosylmethylisocyanides in a microwave-assisted Van Leusen three-component condensation. Subsequent unmasking (Boc removal) of an internal amino-nucleophile promotes deprotection and cyclization that take place either spontaneously in a one-pot fashion to give 8 or upon acidic treatment under microwave irradiation after isolation of the imidazole intermediate to give 11. Of note, a tricyclic framework is hence assembled by means of a rapid and straightforward method with a high bond-forming efficiency.

This Letter presents the synthesis and biological evaluation of a collection of 2-aminothiazoles as a novel class of compounds with the capability to reduce the production of PGE2 in HCA-7 human adenocarcinoma cells. A total of 36 analogs were synthesized and assayed for PGE2 reduction, and those with potent cellular activity were counter screened for inhibitory activity against COX-2 in a cell free assay. In general, analogs bearing a 4-phenoxyphenyl substituent in the R2 position were highly active in cells while maintaining negligible COX-2 inhibition. Specifically, compound 5l (R1 = Me, R2 = 4-OPh-Ph, R3 = CH(OH)Me) exhibited the most potent cellular PGE2 reducing activity of the entire series (EC50 = 90 nM) with an IC50 value for COX-2 inhibition of >5 μM in vitro. Furthermore, the anti-tumor activity of analog 1a was analyzed in xenograft mouse models exhibiting promising anti-cancer activity.This Letter presents the synthesis and biological evaluation of a collection of 2-aminothiazoles as a novel class of compounds with the capability to reduce the production of PGE2 in HCA-7 colon cancer cells. A total of 36 analogs were tested and active compounds were identified. Furthermore, the anti-tumor activity of analog 1a was analyzed in xenograft mouse models exhibiting promising anti-cancer activity.

A concise two-step procedure for the synthesis of novel δ-lactam tetrazoles has been established via the Ugi-azide reaction using 5-oxohexanoic acid along with primary amines, isocyanides, and azidotrimethylsilane followed by 1,1′-carbonyldiimidazole-mediated intramolecular amide formation. Expansion to \({\varepsilon}\)-lactam tetrazole scaffolds was accomplished using methyl 6-oxoheptanoate via the same Ugi-azide reaction followed by basic hydrolysis and SOCl2 activation to enable lactam formation.

Concise routes to five pharmacologically relevant bis-heterocyclic scaffolds are described. Significant molecular complexity is generated in a mere two synthetic operations enabling access to each scaffold. Routes are often improved by microwave irradiation and all utilize isocyanide-based multi-component reaction methods to incorporate the required diversity elements. Common reagents in all initial condensation reactions include 2-(N-Boc-amino)-phenyl-isocyanide 1, mono-Boc-phenylenediamine 2 and ethyl glyoxalate 3.

This Letter reveals an innovative and facile procedure to prepare quinoxalines in two synthetic steps. The microwave assisted Petasis reaction is followed by the acid mediated unmasking of an internal amino nucleophile, cyclodehydration and oxidation to give collections of quinoxalines in good to excellent yields.This Letter reveals an innovative and facile procedure to prepare quinoxalines in two synthetic steps. The microwave assisted Petasis reaction is followed by the acid mediated unmasking of an internal amino nucleophile, cyclodehydration, and oxidation to give collections of quinoxalines in good to excellent yields.

The following article describes a concise synthesis of a collection of 4,5-dihydro-1H-benzo[e][1,4]diazepines fused to a hydantoin ring. Molecular complexity and biological relevance are high and structures are generated in a mere three steps, employing the Ugi reaction to assemble diversity reagents. The protocol represents a novel UDC (Ugi-deprotect-cyclize) strategy employed in the Ugi-5-component CO2-mediated condensation, followed by further cyclization under basic conditions, to afford the fused hydantoin. Mechanistic caveats, dependent on the aldehydes of choice will be revealed and a facile oxidation of the final products to imidazolidenetriones is briefly discussed.The article describes a concise synthesis of a collection of 4,5-dihydro-1H-benzo[e][1,4]diazepines fused to a hydantoin ring, generated in a mere three steps. The protocol employs the Ugi-5-component CO2-mediated condensation, benzodiazepine formation promoted by acidic conditions and basic treatment to afford the fused hydantoin. Mechanistic caveats, dependent on the aldehydes of choice will be revealed and a facile oxidation of the final products to imidazolidenetriones is briefly discussed.

Novel two-step solution phase protocols for the synthesis of dihydroquinazolines and fused dihydroquinazoline-benzodiazepine tetracycles are reported. The methodology employs the Ugi reaction to assemble the desired diversity and acid treatment enables ring-closing transformations. The protocols are further facilitated by the use of microwave irradiation and n-butyl isocyanide to control the rate of each ring-forming transformation.Novel two-step solution phase protocols for the synthesis of dihydroquinazolines and fused dihydroquinazoline-benzodiazepine tetracycles are reported. The methodology employs the Ugi reaction to assemble the desired diversity and acid treatment enables ring-closing transformations. The protocols are further facilitated by the use of microwave irradiation and n-butyl isocyanide to control the rate of each ring-forming transformation.

This review details a now established area within the isonitrile multi-component reaction (IMCR) field of study, namely employing bi-functional reagents in the Ugi reaction for the construction of screening sets with the additional element or even possibly ‘metric’ of enhanced ‘iterative efficiency potential’ The concept of ‘iterative efficiency’ will be briefly introduced, coupled with discussion on new synthetic routes to select bi-functional IMCR precursors and their use in the generation of pharmacologically relevant ‘molecular diversity’

Imidazo-[1,2-x]heterocycles are versatile building blocks for use in both a ‘drug hunters’ quest to discover new leads and a chemical biologists search for effective molecular tools in ‘cell perturbation’ studies. At the front end of the drug discovery flow chart, the last 5–10 years have witnessed the discovery of new high-throughput methodologies which very quickly have enabled access to virtual libraries of these chemo-types in the realm of 107 derivatives. Interestingly, these often neglected cores in patent cooperation treaty (PCT) applications appear in several highly effective marketed drugs, completing the medicinal chemists search for clinical success. Such rigid chemo-types, all containing a bridgehead nitrogen atom, are thus poised for an ever increasing impact on the discovery and development of new molecular therapeutics. The following mini-review will briefly cover therapeutic utility, chemical methodologies and automation developed to enable preparation of arrays of these chemo-types in a high-throughput manner. Synthetic emphasis is placed on a 3-component-3-center isocyanide based multi-component reaction (IMCR), which spans solution, solid phase, flourous and microwave assisted organic synthesis.

A concise one-pot three-component reaction that affords fluorescent indolizines, benzo[d]pyrrolo[2,1-b]thiazoles, and pyrrolo[1,2-a]pyrazines is reported. The methodology involves the formation of a heterocyclic 1-aza-1,3-diene derived from a Knoevenagel condensation between an aldehyde and 2-methyl-ene-cyano aza-heterocycles, followed by [4 + 1] cycloaddition of acetyl cyanide behaving as a non-classical isocyanide replacement.

Herein, a two-step MCR-oxidation methodology accessing decorated 2° α-ketoamides and α-ketotetrazoles is described via a catalytic copper(I)-mediated C–N oxidation/acidic hydrolysis of Ugi-three-component and Ugi-azide reaction products. The ability to install diversity from aldehyde and isocyanide synthons allows rapid complexity generation. Of note, (1) 2° α-ketoamides are traditionally difficult to access and more so reminiscent of the endogenous peptide bonds. (2) The route to α-keto-tetrazoles is significantly shorter than that in previous reports.

1,5-Disubstituted tetrazoles are an important drug-like scaffold known for their ability to mimic the cis-amide bond conformation. The scaffold is readily accessible via substitution of the carboxylic acid component of the Ugi multi-component reaction (MCR) with TMSN3 in what is herein denoted the Ugi-azide reaction. This full paper presents a concise, novel, general strategy to access a plethora of new heterocylic scaffolds utilizing tethered aldo/keto-acids/esters in the Ugi-azide reaction followed by a ring closing event that generates novel highly complex bis-heterocyclic lactam-tetrazoles.