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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
ACS Comb Sci. Author manuscript; available in PMC 2013 August 13.
Published in final edited form as:
PMCID: PMC3426865

A General One-pot, Two-step Protocol Accessing a Range of Novel Polycyclic Heterocycles with High Skeletal Diversity


An Ugi one-pot three-component 4-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: post-condensation, Ugi reaction, benzimidazole, lactams, one-pot


The Ugi multi-component reaction (MCR) and several closely related isocyanide based MCRs1 are useful synthetic tools that are frequently applied in the drug design and development process.2 The fact that the Ugi reaction utilizes four diversity reagents (acid, aldehyde, amine and isocyanide) in one-pot3 makes it ideal for the high-throughput construction of chemical libraries.4 Indeed, a key features associated with such condensations is the process of tethering the diversity reagents in various combinations to generate new heterocyclic chemotypes.5 In this context, the most commonly and successfully used tethered combination comprises an acid and ketone/aldehyde input6 resulting in the formation of lactams of varying ring sizes which have widespread utility in disease modifying small molecules.7 While exploring the potential of Ugi post-condensations, we have previously synthesized a number of novel scaffolds: benzodiazepines,8 benzimidazoles,9 ketopiperazines,10 imidazoline-γ-lactams,11 hydantoins12 and quinazolines13 to name a few.

Herein, we report a post-condensation intramolecular-Ugi strategy that enables production of nitrogen-enriched polycyclic scaffolds endowed with benzimidazoles, lactams of various ring sizes, dihydroquinazolines and other moieties, coalesced within a single constrained molecular architecture. The range and average values of molecular weights (MW), polar surface areas (PSA) and clogP for all target molecules depicted in this article are as follows: [MW 255 to 399, av. 340], [PSA 40 to 63 Å2, av. 47Å2], [clogP 1.1 to 5.1, av. 4.0] and suggesting potential for high oral bioavailability and consequently interest from the file enhancement community. Indeed, there is a plethora of literature invoking the pharmacological relevance of benzimidazole scaffold.14 Encouragingly, many of these compounds have been accepted by the Molecular Libraries Small Molecule Repository (MLSMR) for interrogation of targets of interest nation-wide.


First studies were conducted employing the bi-functional reagent levulinic acid 1{1} in combination with N-Boc-1,2-phenylenediamine 2{1} and pentyl-isocyanide 3{1} using trifluoroethanol (TFE) as solvent to enhance yields of the condensation product (Scheme 1).15

Scheme 1
Synthesis of α-quaternized benzimidazole-carboxamides

After monitoring the Ugi reaction by LCMS, the reaction was found to be complete in 3 h at room temperature affording 4{1,1,1} (72% isolated yield). The Ugi product was subsequently dissolved in a 10% solution of trifluoroacetic acid (TFA) in dichloroethane (DCE) and exposed to microwave irradiation at 120°C for 15 minutes. As such, these conditions promoted an amino-cyclodehydration to render the tricyclic scaffold 6{1,1,1} containing a valuable α-quaternary methyl group (70% isolated yield, 50 % for two steps), Scheme 1.

Heating the reaction mixture for shorter times or at lower temperatures resulted in only partial product formation with the amine 5{1,1,1} being the major product. With this robust protocol inhand, six congeners (6{1,1,1} through 6{2,2,2}) were produced in up to 58% yields for the two overall steps, Figure 1. The comparable yields demonstrate the generic nature of the reaction with no apparent preference for aldehyde-acids over keto-acids or selected tethers under these expedited conditions. These findings prompted us to apply the procedure to aid formation of the chemically more complex scaffolds of generic formulae 9, Scheme 2. Thus, isocyanide 3 (2-(N-Boc-amino)-phenyl-isocyanide) was prepared from N-Boc-1,2-phenylenediamine using standard methodology16 and treated with tethered acids (1{1} to 1{7}) and various amines (2{1} to 2{6}) to form the Ugi adducts of generic structure 7. Exposure of the adducts 7 to the conditions used to promote cyclization in Scheme 2, successfully afforded a range of bis-heterocyclic scaffolds 9 in overall isolated yields of up to 64% (over two steps), Figure 3.

Figure 1
Products 6{1,1,1} through 6{2,2,2}
Figure 3
Products 9{1,1} through 9{3,1}
Scheme 2
Generic scheme for the synthesis of polycyclic scaffolds 9

The developed process was then employed with amines carrying a second masked internal nucleophile (2{1} and 2{2}), isocyanide 3 and tethered bifunctional reagents, 1{1} through 1{4} (Scheme 3). As expected, intramolecular Ugi reactions performed well and gratifyingly subsequent acid treatment of the Ugi adducts (10) and microwave irradiation afforded products 12 in excellent yields in a mere two synthetic operations, Figure 5.

Figure 5
Products 12{1,2} through 12{3,2}
Scheme 3
Synthesis of polycyclic scaffolds 12

Considering the medicinal potential of quinazolines embedded with benzimidazoles, scaffolds of generic structure 12 could be particularly interesting since the calculated values for bioavailabilty criteria fall well within the ideal ranges. Definitive structural elucidation of products 9{4,4} and 12{1,2} was confirmed by X-ray crystallographic analysis, Figure 7.

Figure 7
X-rays structures of compound 9{4,4} and 12{1,2}


A range of tethered keto-acids or aldehyde acids were successfully employed in intramolecular ring forming Ugi reactions, followed by either one or two consecutive amino-cyclodehydrations to afford a range of unique scaffolds with excellent physicochemical properties in a general one pot, two step protocol. These concise routes coupled with attractive final products represent an excellent file enhancement opportunity delivering potential libraries of high ‘skeletal diversity’ with ‘lead-like’ properties.


General procedure for the preparation of benzotetrazolodiazepinones 6

Using 8 mL microwave vial equipped with a magnetic stirring bar, a solution of 0.25 mmol of keto- or formyl acid (1) and 0.25 mmol of N-Boc-diamine (2) in 0.7 mL of trifluoroethanol (TFE) was stirred for a few minutes at room temperature followed by the addition of isocyanide (3) (0.25 mmol). The progress of the reaction was monitored using LCMS and completion of the Ugi reaction was observed after 3 h stirring. The reaction mixture was concentrated using a nitrogen flush and ~2 mL of 10% (v/v) trifluoroacetic acid (TFA) in dichloroethane (DCE) were added. The reaction was heated in a CEM microwave at 120°C for 15 minutes. After cooling the reaction mixture to room temperature, it was directly loaded on a CombiFlash Rf system (silica gel) and using a gradient of ethyl acetate/hexane (0 to 100%) followed by methanol/ethyl acetate (0 to 20%) the product 6 was purified.

General Procedure for Compounds 9

The same procedure as for compounds 6, was used for this series of compounds with the following exceptions: reactions were conducted at 0.5 mmol scale in 3 mL of solvent (TFE) and after the deprotection/cyclization stage, purification was done on a CombiFlash Rf system (silica gel) using a gradient of ethyl acetate/hexane (0 to 100%).

General Procedure for Compounds 12

Exactly the same procedure (as for 9) was employed for the preparation and purification of compounds 12.

Figure 2
Employed diversity reagents, 1, 2 and 3.
Figure 4
Employed diversity reagents, 1 and 2
Figure 6
Employed diversity reagents, 1 and 2

Supplementary Material





The authors are thankful to Gary S. Nichol for X-rays analysis and Nicole Schechter for proofreading.

Funding Sources

This work was supported by the National Institutes of Health (P41GM086190).


multi-component reaction
trifluoroacetic acid
molecular libraries small molecule repository
tertiary butoxy carbonyl



Supporting Information

Supporting information including all experimental procedures, CIF files for compounds 9{4,4} and 12{1,2} and characterization data for all the compounds are available free of charge via the internet at

The Authors declare no competing financial interest.


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