Abstract
This communication 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.
Keywords: Petasis reaction, Multicomponent reaction, Quinoxaline, Intramolecular cyclization, Microwave
Discovered in 1993, the Petasis reaction joined a relatively short list of Type-II multi-component reactions (MCRs) which involve only one irreversible step in their reaction mechanism.1 Interestingly, with competition from a plethora of robust protocols that employ highly reactive organometallic reagents as nucleophilic equivalents, the Petasis reaction is probably underutilized when one considers the complete specificity of boronic acids for the C=N bond relative to the C=O bond.2,3 Indeed, unlike other organometallic reactions, the Petasis reaction is extremely operationally friendly, not requiring special handling, producing only relatively innocuous boric acid as a side product.4 As such, the seminal discovery by Petasis of what is a boronic acid variant of the classical Mannich reaction has demonstrated great value for the production of libraries of small molecules. Such libraries, employing post-Petasis chemical modifications, span arrays of peptidomimetic heterocycles that include piperazinones,5 benzopiperazinones, benzodiazepines, aza-β-lactams6 and dihydroisoquinoline derivatives.7 All the aforementioned strategies utilize post-Petasis modifications to rigidify the initial Petasis product. Of major significance is the application of the Petasis reaction by workers at Merck during the process development of the Substance P antagonist, Apprepitant™, developed as a potential anti-depressant with a new mode of action.8 In somewhat analogous fashion, we have been extensively involved in a number of post-MCR modifications9 which in succint fashion lead to a variety of pharmacologically relevant scaffolds, adopted by many for the preparation of thousands of compounds in a high-through modality for file enhancement of corporate and academic screening collections alike.10
Herein we report a two step Petasis-Deprotection-Cyclodehydration-Oxidation sequence that enables the preparation of quinoxaline congeners in rapid fashion. The route is even more attractive due to the easy access to numerous commercially available diversity reagents. From the perspective of biological relevance, quinoxalines exhibit a large variety of biological activities such as antibacterial,11 antimalarial,12 antifungal,13 and antithrombotic activities.14 Moreover quinoxaline based drugs have shown to be photochemical DNA cleaving agents making them highly attractive and promising scaffolds for anticancer therapeutics15 In addition they have found widespread use in dyes and organic semiconductors.16 Of particular interest to the group, are reported allosteric kinase inhibitors of AKT1, that contain the diarylquinoxaline moiety made accessible through this methodology.17
Our initially explored model Petasis MCR comprised reaction of mono-protected diamine 1, phenylglyoxal 2 and p-tolyl boronic acid 3, carried out in different media at a variety of temperatures. Reaction progress was monitored by LCMS, Table 1. Of the eight solvents and solvent combinations evaluated, dichloromethane and acetonitrile proved optimal, requiring 18 hours at room temperature (> 70% yield) or 15 mins at 120°C irradiated with microwaves (> 90% yield) for acceptable product formation. Under the latter conditions dimethylformamide also proved to be an excellent solvent.
Table 1.
Optimization of the Petasis reaction.a
| Entry | Solvent | Yieldb (%) 0.5 h, rt | Yieldb (%) 18 h, rt | Yieldb (%) 15 min, 120 °C |
|---|---|---|---|---|
| 1 | DMF | <5 | 17% | 97% |
| 2 | DCM | 26 | 84% | 98% |
| 3 | MeCN | 36 | 72% | 91% |
| 4 | Toluene | <5 | 16% | 31% |
| 5 | THF | <5 | <5% | 27% |
| 6 | Ethanol | 16 | <5% | <5% |
| 7 | Dioxane/water (3:1) | 0 | <5% | <5% |
| 8 | MeCN/DMF (1:1) | 5 | 24% | 87% |
All the reactions were carried out at 0.1 mmol scale.
LCMS Area% purity as judged by Evaporative Light Scattering (ELS).
Summarizing, it is clear that protic solvents whether used alone or in combination were unsuited to optimal progression of the Petasis reaction (Table 1, Entries 6, 7). Likewise toluene and tetrahydrofuran afforded only modest yields of desired product (Table 1, Entries 4, 5), whilst DMF, dichloromethane and acetonitrile proved to be almost equally effective as solvents (Table 1, Entries 1, 2, 3). For operational ease, dichloromethane was selected as solvent of choice for further studies.
Folling optimization of the Petasis conversion, a variety of reagents were quickly screened to unmask the internal nucleophile present on the Petasis product and trigger simultaneous cyclization onto the carbonyl group derived from phenylglyoxal and oxidation to the quinoxalinone. Differing combinations of dehydrating and/or drying agents and solvents were evaluated at room temperature, Table 2. Somewhat predictably both TFA/DCE and HCl/EtOAc systems resulted in excellent yields of the quinoxaline product (Table 2, Entries 6, 7). However, due to its milder nature, the TFA/DCE combination seemed to be superior since prolonged exposure of reaction mixtures to HCl/EtOAc solution resulted in disintegration of the final quinoxaline. An attempt to speed up the reaction (20% TFA/DCE, 80°C, 15 min., microwave irradiation CEM Explorer™) proved to be counterproductive as the quinoxaline interestingly started to fragment.
Table 2.
Optimization of reaction conditions.a
| Entry | System | Time (h), | Temp (°C), | Yieldb (%) |
|---|---|---|---|---|
| 1 | AcOH/i-PrOH | 18 h | rt | <5 |
| 2 | PTSA/DCM | 18 h | rt | 18 |
| 3 | PTSA/MgSO4/DCM | 18 h | rt | 6 |
| 4 | PTSA/TFA/DCE | 18 h | rt | 25 |
| 5 | TFA/DCC/DCE | 18 h | rt | 14 |
| 6 | TFA/DCE | 18 h | rt | 100 |
| 7 | HCl/EtOAc | 18 h | rt | 99 |
| 8 | TFA/DCE | 0.25 h | 80°C | 72 |
All the reactions were carried out at 0.1 mmol scale.
LCMS Area% purity as judged by Evaporative Light Scattering (ELS) yield.
Subsequently, the reaction scope in terms of substrate tolerance was explored. Various glyoxaldehydes and boronic acids having different substituents (both electron withdrawing and donating groups) were screened (mainly using mono-N-Boc-protected o-phenylene-diamine as the amine equivalent). The Petasis reaction showed good to excellent yields in most examples, regardless of the electronic or steric properties of the boronic acid or glyoxaldehydes used (Table 3, Entries 1-3, 5, 7, 9 and 10). Noticeably, however, using a highly hindered glyoxaldehyde (2, 4, 6-trimethyl glyoxaldehyde) proved to be detrimental showing no Petasis product at all (Table 3, Entries 4, 8). On the contrary, a highly sterically hindered boronic acid had much lower, if any impact on the Petasis reaction (Table 3, Entry 9). Furthermore, under the conditions employed boronic acids of a non-aryl origin were seen to poorly perform in the Petasis reaction (Table 3, Entry 6). Replacing N-Boc-protected o-phenylene-diamine with 3,4-dimethyl N-Boc-protected o-phenylene-diamine resulted in relatively lower yields than normal for the Petasis reaction (Table 3, Entries 11, 12), as can be seen by comparing yields of Entry 9 and 12. Attempts to expand the scope of accessible chemotypes to potentially pyrazines via use of N-Boc-ethylene-diamine were unsatisfactory due to very low Petasis reaction yields.18
Table 3.
Reactivity domain for Petasis/Deprotection/Cyclodehydration/Oxidation protocol.a
| Entry | R1 | R2 | R3 | Yield (%) (4a – 4l) |
Yield (%) (5a – 5l) |
|---|---|---|---|---|---|
| 1 | H | 4-F-Ph | 4-Me-Ph | 57 (4a) | 98 (5a) |
| 2 | H | 4-CF3-Ph | 4-Me-Ph | 49 (4b) | 92 (5b) |
| 3 | H | Ph | 3-F-Ph | 48 (4c) | 77 (5c) |
| 4 | H | 2,4,6-tri-Me-Ph | 2-MeO-Ph | 0 (4d) | nd (5d) |
| 5 | H | 4-CF3-Ph | 2-Naphthyl | 71 (4e) | 91 (5e) |
| 6 | H | Ph | trans-β-Styryl | 39 (4f) | nd (5f) |
| 7 | H | Ph | 2-MeO-Ph | 63 (4g) | 85 (5g) |
| 8 | H | 2,4,6-tri-Me-Ph | 4-Me-Ph | 0 (4h) | nd (5h) |
| 9 | H | Ph | 2,4,6-tri-F-Ph | 83 (4i) | 98 (5i) |
| 10 | H | 4-CF3-Ph | 3-CF3-Ph | 87 (4j) | 81 (5j) |
| 11 | CH3 | 4-CF3-Ph | 2-Naphthyl | 45 (4k) | 93 (5k) |
| 12 | CH3 | Ph | 2,4,6-tri-F-Ph | 24 (4l) | 35 (5l) |
All the reactions were carried out at a 1 mmol scale and isolated yields are reported. [Note: nd = not determined].
In contrast to the Petasis reaction the subsequent deprotection-cyclodehydration-oxidation sequence worked smoothly furnishing products in excellent yields for nearly all examples.19
In conclusion, we have reported a short, convenient and robust two step procedure to prepare diversified quinoxalines. Use of microwave makes this process more attractive since reaction time has been considerably diminished for a usual Petasis reaction. Current efforts are focusing on optimizing routes to additional chemotypes of pharmacological importance.
Scheme 1. Model Petasis Reaction.
Scheme 2. Boc removal and cyclodehydration-oxidation.
Scheme 2. Two step sequence to Quinoxalines.
Acknowledgments
We would like to thank the Office of the Director, NIH, and the National Institute of Mental Health for funding (1RC2MH090878-01).
Footnotes
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
References and Notes
- 1.Petasis NA, Akritopoulou I. Tetrahedron Lett. 1993;34:583–586. [Google Scholar]
- 2.Bloch R. Chem Rev. 1998;98:1407–1438. doi: 10.1021/cr940474e. [DOI] [PubMed] [Google Scholar]
- 3.Matteson DS. Stereodirected Synthesis with Organoboranes. Springer-Verlag; Berlin: 1995. [Google Scholar]
- 4.Wallace DJ, Chen CY. Tetrahedron Lett. 2002;43:6987–6990. [Google Scholar]
- 5.Petasis NA, Patel ZD. Tetrahedron Lett. 2000;41:9607–9611. [Google Scholar]
- 6.Naskar D, Roy A, Seibel WL, Portlock DE. Tetrahedron Lett. 2003;44:6297–6300. [Google Scholar]
- 7.Grigg R, Sridharan V, Thayaparan A. Tetrahedron Lett. 2003;44:9017–9019. [Google Scholar]
- 8.Pye PJ, Rossen K, Weissman SA, Maliakai A, Reamer RA, Ball R, Tsou NN, Volante RP, Reider PJ. Chem Eur J. 2002;8:1372–1376. doi: 10.1002/1521-3765(20020315)8:6<1372::aid-chem1372>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
- 9.(a) Hulme C, Tang S, Burns C, Labaudiniere R. J Org Chem. 1998;63:8021–8023. [Google Scholar]; (b) Hulme C, Gore V. Current Med Chem. 2003;10:51–80. doi: 10.2174/0929867033368600. [DOI] [PubMed] [Google Scholar]; (c) Hulme C, Nixey T. Current Opinion in Drug Discovery Today. 2003;6:921–929. [PubMed] [Google Scholar]; (d) Xu Z, Dietrich J, Shaw AY, Hulme C. Tetrahedron Lett. 2010;51:4566–4569. doi: 10.1016/j.tetlet.2010.06.116. [DOI] [PMC free article] [PubMed] [Google Scholar]; (e) Gunawan S, Nichol GS, Chappeta S, Dietrich J, Hulme C. Tetrahedron Lett. 2010;51:4689–4692. doi: 10.1016/j.tetlet.2010.06.131. [DOI] [PMC free article] [PubMed] [Google Scholar]; (f) Dietrich J, Kaiser C, Meurice N, Hulme C. Tetrahedron Lett. 2010;51:3951–3955. doi: 10.1016/j.tetlet.2010.05.108. [DOI] [PMC free article] [PubMed] [Google Scholar]; (g) Hulme C, Lee YS, Chappetta S, Dietrich J. Tetrahedron Lett. 2009;50:1939–1942. [Google Scholar]; (h) Hulme C, Chappetta S, Dietrich J. Tetrahedron Lett. 2009;50:4054–4057. [Google Scholar]
- 10.Hulme C, Bienayme H, Nixey T, Chenera B, Jones W, Tempest P, Smith A. Methods in Enzymology. Vol. 369. Elsevier Inc; New York: 2003. pp. 469–496. & references therein. [DOI] [PubMed] [Google Scholar]
- 11.(a) Ganapaty S, Ramalingam P, Rao CB. Indian J Heterocycl Chem. 2007;16:283–286. [Google Scholar]; (b) Refaat HM, Moneer AA, Khalil OM. Arch Phram Res. 2004;27:1093–1098. doi: 10.1007/BF02975110. [DOI] [PubMed] [Google Scholar]; (c) Badran MM, Abouzid KAM, Hussein MHM. Arch Pharm Res. 2003;26:107–113. doi: 10.1007/BF02976653. [DOI] [PubMed] [Google Scholar]; (d) Nasr MNA. Arch Pharm Med Chem. 2002;8:389–394. doi: 10.1002/1521-4184(200211)335:8<389::AID-ARDP389>3.0.CO;2-X. [DOI] [PubMed] [Google Scholar]; (e) El-Hawash SA, Habib Ns, Fanaki NH. Pharmazie. 1999;54:808–815. [PubMed] [Google Scholar]; (f) El-Gendy AA, El-Meligie S, El-Ansary A, Ahmedy AM. Arch Pharm Res. 1995;18:44–47. [Google Scholar]
- 12.(a) Rangisetty JB, Gupta CN, Gupta CNVHB, Prasad AL, Srinivas P, Sridhar N, Parimoo P, Veeranjaneyulu A. Pharmacy and Pharmacology. 2001;53:1409–1413. doi: 10.1211/0022357011777765. [DOI] [PubMed] [Google Scholar]; (b) Crowther AF, Curd FHS, Davey DG, Stacey GJ. J Chem Soc. 1949:1260–1262. [Google Scholar]
- 13.Tandon VK, Yadav DB, Maurya HK, Chaturvedi AK, Shukla PK. Bioorg Med Chem. 2006;14:6120–1626. doi: 10.1016/j.bmc.2006.04.029. [DOI] [PubMed] [Google Scholar]; Sanna P, Carta A, Loriga M, Zanetti S, Sechi L. Farmaco. 1999;54:1169–1177. doi: 10.1016/s0014-827x(99)00010-5. [DOI] [PubMed] [Google Scholar]
- 14.Ries UJ, Priekpe HW, Havel NH, Handschuh S, Mihm G, Stassen JM, Wienen W, Nar H. Bioorg Med Chem Lett. 2003;13:2297–2302. doi: 10.1016/s0960-894x(03)00443-8. [DOI] [PubMed] [Google Scholar]
- 15.Toshima K, Kimura T, Takano R, Ozawa T, Ariga A, Shima Y, Umezawa K, Matsumura S. Tetrahedron. 2003;59:7057–7066. [Google Scholar]
- 16.Dailey S, Feast WJ, Peace RJ, Sage IC, Till S, Wood EL. J Mater Chem. 2001;11:2238–2243. [Google Scholar]
- 17.Lindsley CW, Zhao Z, Leister WH, Robinson RG, Barnett SF, Defeo-jones D, Jones RE, Hartman GD, Huff JR, Huber HE, Duggan ME. Bioorg Med Chem Lett. 2005;15:761–764. doi: 10.1016/j.bmcl.2004.11.011. [DOI] [PubMed] [Google Scholar]
- 18.Using 4-methylphenyl boronic acid, phenyl glyoxaldehyde and N-Boc-ethylenediamine gave a complex mixture from the Petasis reaction with a negligible amount of the desired product. Similarly in Table 3, Entry 3, replacing phenyl glyoxaldehyde with methyl glyoxaldehyde showed only 23% of the desired Petasis product: none of the reactions was considered for purification or subsequent deprotection/cyclization steps.
- 19.General procedure for preparation of 5c: 1 mmol of each diamine, glyoxaldehyde and boronic acid were taken into a microwave vial already equipped with a magnetic bar. 1 mL of dichloromethane was added to the system followed by heating it at 120 °C for 15 minutes. The crude Petasis product was then directly loaded to an ISCO™ purification system and using ethylacetate/hexane as eluent (0 to 100% gradient over 25 minutes) the products were purified. A weighed out amount of Petasis product (0.10 to 0. 30 mmol) was then subjected to 1-2 mL of 20% TFA in dichloromethane. The reaction was stirred for ∼18 hours at room temperature, evaporated in vacuo and crude material purified via chromatography (ISCO™) to afford the desired product (77% yield) as a white solid. Quinoxaline 5c: Rf 0.55 (Hexane/AcOEt 8:2). 1H NMR (400 MHz, CDCl3): δ = 8.17-8.21 (m, 2H), 7.79-7.82 (m, 2H), 7.50-7.54 (m, 2H), 7.21-7.39 (m, 6H), 7.04-7.09 (m, 1H). 13C NMR (100 MHz, CDCl3): δ = 163.8, 161.2, 153.1, 141.3, 140.9, 138.6, 130.3, 130.1, 129.8, 129.7, 129.6, 129.2, 129.2, 129.0, 128.4, 125.7, 116.9, 116.7, 115.9, 115.7. ESI 301 (MH+).