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. Author manuscript; available in PMC: 2011 Sep 8.
Published in final edited form as: Tetrahedron Lett. 2010 Sep 8;51(36):4689–4692. doi: 10.1016/j.tetlet.2010.06.131

Concise Preparation of Novel Tricyclic Chemotypes: Fused Hydantoin-benzodiazepines

Steven Gunawan 1, Gary S Nichol 2, Shashi Chappeta 3, Justin Dietrich 4, Christopher Hulme 5,*
PMCID: PMC2928152  NIHMSID: NIHMS226189  PMID: 20802841

Abstract

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 is 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 aldehydes of choice will be revealed and a facile oxidation of final products to imidazolidenetriones briefly discussed.

Operationally friendly protocols to produce libraries of novel small molecules of high molecular complexity are in huge demand for the interrogation of biological systems.1 As such, development of new MCRs (multi-component reactions) and functional group modification of MCR products have proven fruitful tools in the quest for new molecular probes and their expedited progression along the drug discovery value chain.2 Such products, of high-iterative-efficiency potential2 have found their way into numerous corporate compound collections and examples exist of hit to clinic campaigns were final drugs resided in the virtual diversity space of the original hit generation library.3 This communication describes the development of a concise three step synthesis of novel tricyclic 4,5-dihydro-1H-benzo[e][1,4]diazepines fused to an hydantoin ring and employs the rarely used 5-component Ugi reaction (U-5-CR), Scheme 1. Essentially, CO2 in MeOH produces carbonic acid and the reaction follows the widely accepted classical Ugi mechanism, even though the condensation product differs in that a urethane is now encapsulated within the final skeleton 1. Prior reports on applications of this reaction are scarce4, although our planned strategy builds on an early report from this laboratory which employed the amidic NH of U-5-CR as an internal nucleophile to afford fully functionalized libraries of hydantoins in a mere two steps.4a

Scheme 1.

Scheme 1

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5-component CO2 modified Ugi reaction

A summary of the generic scaffolds 2 and 3 made accessible and introduced in this article is shown in Figure 1. Thus, construction of the desired Ugi precursor 6 is achieved via condensation of ortho-N-Boc benzylamines 4, phenylglyoxaldehydes 5, isonitriles and a saturated solution of CO2 in methanol, Scheme 2. Note that 4 was prepared in 3 steps from commercially available 2-aminobenzylamine as portrayed in Scheme 3 according to the referenced procedure.5 Purified Ugi product is subsequently treated with trifluoroacetic acid promoting amine deprotection and cyclization to the 4,5-dihydro-1H-benzo[e][1,4]diazepine, 7 typically in good yield (> 90%). Note that this transformation extends the repertoire of available chemotypes from UDC (Ugi/DeBoc/Cyclize) methodology and libraries of this benzodiazepine should now be readily accessible. Final ring construction was achieved by treatment of 7 with KOH, thus promoting cyclization and fusion of a hydantoin-like ring whilst simultaneously initiating a 1,3-H shift to give the tricyclic chemotype 8 in good yield. As such, the methodology represents an example of a post-condensation Ugi modification4a that employs two internal nucleophiles in distinct operations, generating a novel scaffold of high complexity in a succint 3 functional operations.

Figure 1.

Figure 1

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Generic scaffolds of 4,5-dihydro-1H-benzo[e][1,4]diazepines fused to a hydantoin ring 2 and imidazolidenetriones 3

Scheme 2.

Scheme 2

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Preparation of fused benzodiazepine-hydantoins

Scheme 3.

Scheme 3

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Synthesis of Boc-2-aminobenzylamine 4

With a satisfactory protocol to the generic structure 8 in place6, a small collection of these molecules were prepared to demonstrate the generality of the reaction sequence, Figure 2. Diversification was based on the commercial availability of different isonitriles and substituted phenylglyoxaldehydes. Reported percent yields represent conversions of the two combined steps from the Ugi product 6 to scaffold 8. In essence, scaffold 7 did not require purification, thus simplifying the production protocol. Unequivocal evidence for the structure of this chemotype was provided by X-ray crystallography for 9.7

Figure 2.

Figure 2

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Example Analogs (x% = Ugi yield, x% = yield of 8 from 6)

Interestingly, the tri-cyclic scaffolds 8 underwent a chemical oxidative transformation to the pharmacologically relevant imidazolidinetriones8 3 (Scheme 4) on standing in CDCl3. One particular example 9 showed 75% conversion to its imidazolidinetrione congener after 10 days in CDCl3. Oxidative carbon-carbon double bond cleavage of similar hydantoin derivatives has been previously reported9 and compound 9 was successfully proven to undergo such oxidation upon treatment with KMnO4.10 Encouragingly for future screening efforts the fused hydantoin compounds are stable in DMSO and other solvents, with no oxidation detected over prolonged periods in solution. As supported by a previous study11, this finding exemplifies the phenomenom of air oxidation in chloroform, suggested to be far more facile than in other regularly used solvents. Oxidative rate acceleration of 9 by light suggests a singlet oxygen mechanism may be involved in this process.

Scheme 4.

Scheme 4

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Aerobic chemical transformations of 8 on standing in CDCl3

Note an exception was found with compound 16, an analog derived from 2-methoxyphenylglyoxaldehyde. Interestingly, a second product was also observed during exposure to CDCl3 (16a:16b = 1:4.5). Tentatively, the following mechanism, Scheme 5, is proposed that involves aromatic substitution with water, tautomerization/rearomatization and oxidation to the imine, 16b. Evidence for this structure was provided by detailed NMR studies.

Scheme 5.

Scheme 5

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Proposed mechanism involving (i) aromatic substitution, (ii) tautomerization-rearomatization and (iii) oxidation to the imine

In summary, a concise 3-step synthesis of a collection of fused 4,5-dihydro-1H-benzo[e][1,4]diazepines-hydantoins has been successfully developed that utilizes the scarcely employed 5-component CO2 modified Ugi reaction as the diversity generating event followed by two subsequent cyclization transformations. The first transformation occurs under acidic conditions to construct the benzodiazepine ring and is followed by a second cyclization under basic conditions to afford the fused hydantoin. Because of the uniqueness of these scaffolds, the desirable drug-like properties of the molecules generated, and the ease of synthesis, this methodology represents a viable strategy for future enrichment of small molecule compound libraries.

Figure 3.

Figure 3

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X-ray crystal structure of 9

Acknowledgments

We would like to thank the Office of the Director, NIH and the National Institute of Mental Health for funding (1RC2MH090878-01). Abbott Laboratories are also thanked for a New Faculty Award to CH.

Footnotes

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Contributor Information

Steven Gunawan, The Southwest Comprehensive Center for Drug Discovery and Development, College of Pharmacy, Department of Pharmacology/Toxicology, The University of Arizona, Tucson, AZ 85721.

Gary S. Nichol, Department of Chemistry and Biochemistry, The University of Arizona, Tucson, AZ 85721

Shashi Chappeta, The Southwest Comprehensive Center for Drug Discovery and Development, College of Pharmacy, Department of Pharmacology/Toxicology, The University of Arizona, Tucson, AZ 85721.

Justin Dietrich, The Southwest Comprehensive Center for Drug Discovery and Development, College of Pharmacy, Department of Pharmacology/Toxicology, The University of Arizona, Tucson, AZ 85721.

Christopher Hulme, The Southwest Comprehensive Center for Drug Discovery and Development, College of Pharmacy, Department of Pharmacology/Toxicology, The University of Arizona, Tucson, AZ 85721.

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