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. Author manuscript; available in PMC: 2013 Mar 28.
Published in final edited form as: Tetrahedron Lett. 2012 Jan 28;53(13):1664–1667. doi: 10.1016/j.tetlet.2012.01.080

Concise route to a series of novel 3-(tetrazol-5-yl)quinoxalin-2(1H)-ones

Steven Gunawan †, Gary Nichol ‡, Christopher Hulme †,*
PMCID: PMC3374393  NIHMSID: NIHMS352936  PMID: 22707799

Abstract

This report 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.

The emerging need to enrich the national US compound collection has inspired the development of methodology that enables concise access to diverse pharmacologically relevant compounds. The Ugi reaction, probably the premiere example of an isocyanide based MCR, contains 4 reagents namely an amine, aldehyde, isocyanide and carboxylic acid. In addition to the development of new MCRs, tremendous efforts have been made by several groups with strategies entailing intramolecular variants of the Ugi and post condensation modifications of the Ugi product.1 Indeed, such chemistry allows rapid access to new molecular diversity and there are examples of hits being discovered, optimized and entering the clinic without a need to scaffold hop.2 One interesting facet of the classical Ugi reaction is the interchangeability of the carboxylic acid, exemplified by replacement with hydrazoic acid, cyanates, thiocyanates, carbonic acid monoesters, salts of secondary amines, hydrogen sulfide as Na2S2O3, hydrogen sulfide, thiocarboxylic acid, phenol or water.3 All these Ugi variants afford enticing structures for further diversification and possibly the most versatile is the Ugi MCR with azidotrimethylsilane (TMSN3). This reaction affords 1,5-disubstituted tetrazoles 3 (Scheme 1), reported effective bioisosteres for the cis-amide bond conformation.4

Scheme 1.

Scheme 1

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General Ugi-Azide reaction

Indeed, rigidification of the core scaffold from the Ugi-Azide MCR has led to the generation of unique cyclic scaffolds such as ketopiperazine-tetrazoles, azepine-tetrazoles, benzodiazepine-tetrazoles, and quinoxaline-tetrazoles.5 However, there is no report of utilization of the Ugi-Azide MCR to produce a quinoxalinone framework which represents an important biological motif found in antithrombotic agents,6 several inhibitors for metalloproteinase,7 hepatitis C virus,8 glycogen phosphorylase,9 poly(ADP-ribose)polymerase-1,10 cyclin-dependent kinases11 and α-amino-3-hydroxy-5-methylisoxazole propionate receptor (AMPA-R) antagonists.12 A common route to access the quinoxalinone template employs o-phenylenediamine derivatives and glyoxylic acids or glyoxylates.11,13 As part of our on-going venture to generate unique small molecules via the Ugi-Azide MCR, we herein report a concise three-step method utilizing mono-N-Boc-protected-o-phenylenediamine derivatives 4 together with ethyl glyoxalate 5 and isocyanides to synthesize arrays of bis-quinoxalinone tetrazoles 6 (Scheme 2).

Scheme 2.

Scheme 2

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Overall synthesis protocol

Initial pilot efforts were focused on the synthesis of 3-(1-butyl-1H-tetrazol-5-yl)quinoxalin-2(1H)-one 12 (Scheme 3) from N-Boc-1,2-phenylenediamine 7, n-butyl isocyanide 8 and ethyl glyoxalate 5. Using MeOH as solvent proved unfruitful, affording 9, presumably arising from Schiff-base 1 solvent addition. Previous Ugi MCR-related articles suggest trifluoroethanol (CF3CH2OH), a non-nucleophilic protic solvent, as a viable alternative for MeOH.14 Thus, precondensation of ethyl glyoxalate 5 and N-Boc-1,2-phenylenediamine 7 in DCE followed by addition of trifluoroethanol, n-butyl isocyanide 8 and TMSN3 afforded Ugi-tetrazole 10 in moderate yield of 45%. Subsequent acid treatment removed the Boc group and the unmasked amine immediately cyclized to form dihydroquinoxalinone 11 in 67% yield. A number of synthetic operations have been reported for quinoxalinone oxidation from dihydroquinoxalinones that include DDQ6b, H2O2-NaOH,15 MnO2,16 p-chloroanil17 and air oxidation.18 Fortuitously, the bis-quinoxalinone tetrazole 12 was attained using a stable solid-phase radical catalyst TEMPO and catalytic CAN under aerobic conditions. This method simplified the work-up to filtration of catalyst and solvent extraction of the oxidized product. To the best of the author’s knowledge, this is the first example of dihydroquinoxalinone oxidation by means of TEMPO, typically employed for the oxidization of primary and secondary alcohol.19 Encouragingly, compound 11 did not require purification and was moved forward in crude form to provide 12 in 63% yield in two steps (10 to 12).

Scheme 3.

Scheme 3

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Synthesis of 3-(1-butyl-1H-tetrazol-5-yl)quinoxalin-2(1H)-one 12

With compound 12 in hand, a series of eleven bis-quinoxalinone tetrazoles 15 were prepared to establish the generality of the reaction sequence. The procedure represents an example of a post-condensation Ugi-Azide modification that utilizes one internal nucleophile with two points of diversity arising from mono-N-Boc-protected-o-phenylenediamine derivatives 13 and isocyanides 14, generating a novel structure in a concise three-step process. Various mono-N-Boc-protected-o-phenylenediamine derivatives 13a–d were employed in library production and synthesized via Boc protection from the diamine. Table 1 summarizes the isolated yields with corresponding diversity inputs. Definitive structural confirmation for this chemotype was provided by X-ray crystallography 15d20 (Figure 1).

Table 1.

Arrays of bis-quinoxalinone tetrazoles 15

graphic file with name nihms352936t1.jpg
13 14 Product Ugi
(%)		 Final Yield* (%)
graphic file with name nihms352936t2.jpg 13a graphic file with name nihms352936t3.jpg 15a 73 58
graphic file with name nihms352936t4.jpg 13a graphic file with name nihms352936t5.jpg 15b 41 66
graphic file with name nihms352936t6.jpg 13a graphic file with name nihms352936t7.jpg 15c 41 47
graphic file with name nihms352936t8.jpg 13b graphic file with name nihms352936t9.jpg 15d 48 49
graphic file with name nihms352936t10.jpg 13b graphic file with name nihms352936t11.jpg 15e 47 47
graphic file with name nihms352936t12.jpg 13b graphic file with name nihms352936t13.jpg 15f 49 59
graphic file with name nihms352936t14.jpg 13b graphic file with name nihms352936t15.jpg 15g 31 62
graphic file with name nihms352936t16.jpg 13c graphic file with name nihms352936t17.jpg 15h 62 41
graphic file with name nihms352936t18.jpg 13c graphic file with name nihms352936t19.jpg 15i 47 47
graphic file with name nihms352936t20.jpg 13c graphic file with name nihms352936t21.jpg 15j 50 43
graphic file with name nihms352936t22.jpg 13d graphic file with name nihms352936t23.jpg 15k 60 27
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*

Two steps for deprotection-cyclization with TFA and oxidation using CAN-TEMPO from Ugi product

Figure 1.

Figure 1

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X-Ray crystal structure of 15d

For further extension, application of this methodology to N-Boc-2-aminobenzylamine21 16 offered an opportunity to access benzodiazepine scaffolds. When 16 was mixed with TMSN3, ethyl glyoxalate 5 and n-butyl isocyanide 8 in MeOH, the MCR-derived tetrazole 17 was isolated in 48% yield (Scheme 4). Unexpectedly, acid treatment of 17 only afforded 18. Attempts to cyclize 18 to 19 through aminolysis of the ester by either activating the ester22 or the amine23 were also unsuccessful. Ultimately, hydrolysis of 18 was performed under basic conditions followed by an EDC-promoted intramolecular amide coupling to provide 19 in 35% (three steps).

Scheme 4.

Scheme 4

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Synthesis of 3-(1-butyl-1H-tetrazol-5-yl)-4,5-dihydro-1H-benzo[e][1,4]diazepin-2(3H)-one 19

In conclusion, a succinct three-step synthesis of a collection of 3-(tetrazol-5-yl)quinoxalin-2(1H)-ones 6 that employs the Ugi-Azide MCR followed by cyclization under acidic condition and immediate oxidation with TEMPO/CAN under aerobic ocnditions has been reported. The method was expanded to afford bis-benzodiazepine tetrazole 19 using N-Boc-2-aminobenzylamine 16 in the Ugi-Azide MCR followed by sequential acid-base treatment and EDC-mediated benzodiazepine formation. Due to the uniqueness of these chemotypes, the promising pharmacological properties, and the ease of synthesis, these procedures offer new feasible strategies for file enhancement by the medicinal chemist.

Acknowledgements

The authors thanked the Office of the Director, NIH and the National Institute of Mental Health for funding (1RC2MH090878-01), Kristen Keck for compound purification, Alex Laetsch for compound management and Nicole Schechter for proof-reading.

Footnotes

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