Metal-free synthesis

While the studies outlined in Eqs. (11.1)-(11.8) summarize the most important frontiers for metal-free synthesis, they also highhght a common limitation for the organocatalysis field. To date, there remain relatively few (less than 10) activation mechanisms that have been established to be amenable to organic catalysis. Accordingly, a primary objective for the advancement of the field of asymmetric organocatalysis has been the design and/or development of concepts that enable organic substrates to function as catalysts for a wide variety of new and established reactions. 

Yonker, C. R. and Linehan, J. C., A high-pressure NMR investigation of reaction chemistries in a simple salt hydrate,. Supercrit. Fluids, 29, 257 2004. Mehnert, C. R, Supported ionic liquid catalysis, Chem. Eur. ]., 11,50,2005. Giernoth, R. and Bankmann, D., Transition-metal free synthesis of perdeuter-ated imidazolium ionic liquidsby alkylation and H/D exchange, Eur. J. Org. Chem., 2008 (in print). DOT 10.1002/ejoc.200700784. 

The C-H transformation in the synthesis of fine chemicals can be separated in reactions employing catalysis by organometallic compounds and metal-free synthesis. Organometallic catalyzed functionalization is usually performed in liquid or gas/liquid reactions whereas the metal-free synthesis of fine chemicals often occurs as a gas-phase reaction. 

Dichiarante, V., Fagnoni, M. and Albini, A. (2007) Metal-free synthesis of sterically crowded biphenyl by direct Ar-H substitution in alkyl benzenes. Angewandte Chemie, International Edition, 46, 6495-6498. 

The synthesis of aza-oxa crown ethers is best accomplished by making carbon-nitrogen bonds in the cyclisation step. Although the original syntheses operated under conditions of high dilution and involved the co-condensation of a diamine with a diacid chloride, these methods have been supplanted by the more versatile and convenient A-alkylation pathways involving toluene-sulfonamide or TV-benzyl intermediates. This chapter has focused on the metal-free synthesis of saturated aza-oxa crown ethers. There are a large number of examples of the synthesis of aromatic and heterocyclic aza-oxa crown ethers that involve the co-condensation of aldehydes and amines mediated by metal ions such as Pb2+ and Ba2+24,25 This in situ synthetic... 

Olofsson and coworkers have developed a general and high-yielding synthesis of various diaryl ethers 681 using the reaction of diaryliodonium salts with phenols under basic conditions (Scheme 3.273) [874]. The scope of products includes bulky orf/io-substituted diaryl ethers, which are difficult to obtain by metal-catalyzed protocols. A similar procedure has been used for the metal-free synthesis of aryl esters from carboxylic acids and diaryliodonium salts [875]. 

Reproduced with permission from Mukherjee N, Chatterjee T, Ranu BC. Reaction under ballmilling solvent-, ligand-, and metal-free synthesis of unsymmetrical diaryl chalcogenides. J Org Chem 2013 78 11110-4, Copyright 2013, American Chemical Society. 

The Ma group devised a facile, an inexpensive, and a metal-free synthesis of pyridazino[4,5-l>][l,4]thiazine-diones 27 via a Smiles rearrangement, obtaining the desired products in high yields (Scheme 11) (13TL3253). Optimal reaction conditions were determined to be treatment of 4,5-dichloro-2-(tetrahydro-2f/-pyran-2-yl)pyridazin-3(2fJ)-one 28 with an N-substituted mercaptoacetamide 29 at room temperature in the presence of cesium carbonate as the base and N,ALdimethylformamide (DMF) as the solvent. The authors foresee future applications of this method to the preparation of biologically active compounds. 

Multiple more environmentally safe protocols were reported in 2013. The Karade group described a facile, mild, transition-metal-free synthesis... 

However, all synthetic approaches involving ATRP rely on a metal catalyst. Full metal-free and thus greener approaches to block copolymers were realized by the combination of Upase ROP with nitroxide-mediated living free radical polymerization [44]. With this system it was also possible to successfully perform a one-pot chemoenzymatic cascade polymerization from a mixture containing a dual initiator, CL and styrene (Fig. 12). Moreover, it was shown that this approach is compatible with the stereoselective polymerization of 4-methylcaprolactone for the synthesis of chiral block copolymers. A metal-free synthesis of block copolymers using a radical chain transfer agent as a dual initiator in enzymatic ROP to yield poly(CL-f -styrene) was also reported recently [119]. 

Das B, Bhunia N, Lingaiah MA (2011) Simple and elficient metal-free synthesis of tetra-substituted pyrroles by iodine-catalyzed four-component coupling reaction of aldehydes, amines, dialkyl acetylenedicarboxylates, and nitromethane. Synthesis 2011 3471-3474 Khan AT, Ghosh A, Khan MM (2012) One-pot four-component domino reaction for the synthesis of substituted dihydro-2-oxypyrrole catalyzed by molecular iodine. Tetrahedron Lett 53 2622-2626... 

Herein, the authors describe recent advances in hypervalent iodine-induced oxidative coupling reactions as a new strategic choice for metal-free synthesis, and their early applications in natural product synthesis used as the key reactions are summarized. We first briefly outline the fundamental hypervalent iodine-induced reactions and then illustrate the examples of their application to the syntheses of various biologically active compounds, such as natural products. 

Scheme 22 (a) Activation of sp C-H bonds, (b) Metal-free synthesis of diarylketones... 

The reaction of A-arylacrylamides and simple alcohols in the presence of 70% aqueous solution of TBHP leads to metal-free synthesis of 3,3-disubstituted oxindoles. A series of hydroxyl-containing oxindole derivatives could be prepared using this method. The reaction is proposed to proceed through an oxidative radical cyclization mechanism and shows excellent functional group tolerance." ... 

Wang Y, Watson MD (2006) Transition-metal-free synthesis of alternating thiophene-perfluoroarene copolymers. J Am Chem Soc 128 2536—2537... 

Rueping M, Stoeckel M, Sugiono E, Theissmann T (2010) Asymmetric metal-free synthesis of fluoroquinolones by organocatalytic hydrogenation. Tetrahedron 66 6565-6568... 

Mamedov VA, Zhukova NA, Beschastnova TN, Zakirova El, Kad3TOva SF, Mironova EV, Nikonova AG, Latypov ShK, Litvinov lA (2012) An efficient metal-free synthesis of 2-(pyrazin-2-yl)benzimidazoles from quinoxalinones and diaminomaleonitrile via a novel rearrangement. Tetrahedron Lett 53(3) 292-296. doi 10.1016/j.tetlet.2011.11.013... 

Transition-Metal Free Synthesis of BenzO Fused Five- and Six-Membered Heterocycles Employing Arynes... 

TRANSITION-METAL-FREE SYNTHESIS OE BENZO-FUSED FIVE- AND SIX-MEMBERED HETEROCYCLES EMPLOYING ARYNES... 

P. Kothandaraman, S.J.L. Lauw, P.W.H. Chan, Metal-free synthesis of lH-indole-2-carbaldehydes by N-iodosucdnimide-rnediated cycUza-tion of l-(2 -aniHnyl)prop-2-yn-l-ols in water a formal synthesis of (R)-calindol, Tetrahedron 69 (2013) 7471-7480. 

M. Nagaraj, M. Boominathan, S. Muthusubramanian, N. Bhuvanesh, Microwave-assisted metal-free synthesis of 2,8-diaryl-6-aminoimid-azo-[l,2-a]pyridine via amine-triggered benzannulation, Synlett (2012) 1353-1357. 

L. Liu, H. Lu, H. Wang, C. Yang, X. Zhang, D. Zhang-Negrerie, Y. Du, K. Zhao, PhI(OCOCF3)2-mediated C-C bond formation concomitant with a 1,2-aryl shift in a metal-free synthesis of 3-arylquinolin-2-ones, Org. Lett. 15 (2013) 2906-2909. 

Y.S. Wagh, N.J. Tiwari, B.M. Bhanage, Metal-free synthesis of 2-aminobenzoxazoles using hypervalent iodine reagent. Tetrahedron Lett. 54... 

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