Anvar Mirzaei

Associate professor, Azad University, Sanandaj, Iran. mirzaei.anvar@gmail.com                


Introduction

Free radical reactions play an important role in synthetic organic chemistry, which establish powerful strategies for the synthesis of a diverse collection of organic compounds [1]. In 1990’s, the Zard and Uemura groups pioneered the use of cyclobutanone oximes as iminyl radical precursors to achieve selective C−C bond cleavage and produce cyanoalkyl radicals [2]. This efficient strategy provided a protocol to gain structurally diverse nitriles [3]. Recently, a series of elegant radical C−C bond cleavages of cycloketone oxime derivatives has been developed by different research groups [4]. During last two decades different protocols for radical C-C bond cleavages of cyclobutanone oxime derivatives have been developed including; transition-metal (Pd, Ir, Fe, Cu, Ni)-catalyzed, microwave-promoted and metal free iminyl radical-involved ring-opening, to construct C–C and C–Y (Y=O, S, N, Se, Te, B) bonds with the synthesis of complex and multifunctionalized nitriles [5].

Radical reactions have several synthetic advantages which make theme interesting in organic synthesis. In the following some of these features will discussed briefly:

1. Carbon-centered radicals are extremely reactive. For example, they can react with Isocyanide as a radical source [6].

Scheme 1: Synthesis of cyclopenta[b]quinoxalines

2. Radical additions to C=C bonds are usually exothermic and irreversible, with early reactant-like transition states. Reactions under kinetic control with early transition states often afford unique products that are unavailable by traditional ionic methods [7].

Scheme 2: Synthesis of cyanoarenes

3. Because radicals are not cluttered with counterions or aggregation spheres, radical intermediates are ideally suited for the synthesis of crowded bonds [8].

Scheme 3: Synthesis of γ-hydroxyalkylated ketones

4. Carbon-centered radicals are inert toward OH or NH groups. Radical reactions do not need to be dry, and the protection of alcohols, amines, and related functional groups is often unnecessary [9].

Scheme 4: Radical aminocarbonylation of cyanoalkyl radical

5. In contrast to carbocations, carbon radicals are subject neither to capture by β-OR or -NR2 groups nor migration or elimination of β-H or -CR3 groups. However, carbon radicals are subject to β elimination of SR, SOnR, and SnR3 groups, and these eliminations are key steps in some synthesis [10].

Scheme 5: Synthesis of cyanoalkylated alkene

Novel synthetic possibilities:

1. Synthesis of phosphoryl butanonitriles: The aim here is to use deconstructive functionalization strategy which involves carbon–carbon (C–C) bond cleavage followed by bond construction on one or more of the constituent carbons. C–C bond cleavage of cycloketone oxime derivatives has emerged as an attractive strategy to construct C–C and C–Y (Y = O, S, Se, Te, or X) bonds [11]. Although remarkable advances have been made, but the C–C bond cleavage/phosphorylation of cyanoalkyl radical remains unexplored.

Scheme 6: Synthesis of phosphoryl butanonitriles

2. Synthesis of fused heterocycles: Nitrogen containing hetero polycycles are a privileged class of structural motifs found in various biologically active natural products and pharmaceutical compounds [12]. Because of their significant properties, chemists have devoted much effort to the synthesis of these aza-heterocycles [13].

Scheme 7: Synthesis of new heterocycles

3. Synthesis of fused carbocycles: In contrast to alkyl radical cyclization onto different double bonds, related closures onto aromatic rings represent a largely undeveloped, and the corresponding closure onto a benzene ring is usually a difficult process [14].

Scheme 8: Synthesis of new fused carbocycles

3. Synthesis of tetrahydrofurans: Tetrahydrofurans represent a class of privileged heterocyclic scaffolds that are found in a plethora of important pharmaceuticals, biologically active natural products, and versatile building blocks in organic synthesis [15].

Scheme 9: Synthesis of tetrahydrofuran derivatives

4. n-butyronitrile radical in MCRs: Multicomponent reactions (MCRs) represent a green approach towards the synthesis of polyfunctionalized molecules by promoting multiple bond-forming mechanisms in a one-pot synthesis [16]. Likewise, the development of radical-mediated, C–C bond-forming transformations has also attracted increasing interest. These protocols usually afford good selectivity, are highly compatible with common functional groups, and often require mild operative conditions [17].

Scheme 10: MCRs of n-butyronitrile

References

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3. (a) Fleming, F. F. Nat. Prod. Rep., 1999, 16, 597. (b) Fleming, F. F.; Wang, Q. Chem. Rev. 2003, 103, 2035.

4. (a) Yang, H.-B.; Selander, N. Chem. – Eur. J. 2017, 23, 1779. (b) Yang, H.-B.; Pathipati, S. R.; Selander, N. ACS Catal. 2017, 7, 8441. (c) Li, L.; Chen, H.; Mei, M.; Zhou, L. Chem. Commun. 2017, 53, 11544. (d) Dauncey, E. M.; Morcillo, S. P.; Douglas, J. J.; Sheikh, N. S.; Leonori, D. Angew. Chem., Int. Ed. 2018, 57, 744. (e) Yu, X.-Y.; Chen, J.-R.; Wang, P.-Z.; Yang, M.-N.; Liang, D.; Xiao, W.-J. Angew. Chem., Int. Ed. 2018, 57, 738.

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11. (a) Zhao, B.; Shi, Z.; Angew. Chem., Int. Ed., 2017, 56, 12727. (b) Gu, Y.-R.; Duan, X.-H.; Yang, L.; Guo, L.-N. Org. Lett. 2017, 19, 5908.

12. (a) Ries, U. J.; Priepke, H. W. M.; Hauel, N. H.; Handschuh, S.; Mihm, G.; Stassen, J. M.; Wienen, W.; Nar, H. Bioorg. Med. Chem. Lett. 2003, 13, 2297. (b) Carta, A.; Piras, S.; Loriga, G.; Paglietti, G. Mini Rev. Med. Chem. 2006, 6, 1179.

13. (a) Mamedov, V. A.; Zhukova, N. A. Prog. Heterocycl. Chem. 2012, 24, 55. (b) Chen, D.; Wang, Z.-J.; Bao, W.-L. J. Org. Chem. 2010, 75, 5768.

14. Clive, D. L. J.; and Rajesh Sunasee, R. Org. Lett. 2007, 9, 2677.

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About the Author

Dr Anvar Mirzaei was graduated from Tarbiat Modares Univesity, Iran. He has worked in Uppsala University, Sweeden during his PhD. He finished his Postdoc in the Chinese University of Hong Kong and has also worked in Hungarian Academy of sciences for a short time.