Kishi-Nozaki-Hiyama reaction

R = alkenyl, aryl, allyl, vinyl, propargyl, alkynyl, allenyl X = Cl, Br, I, OTf, etc. R, R = alkyl, aryl, alkenyl, H  

In the nickel(ll)-catalyzed NHK reaction, the first step is the reduction of Ni to Ni that inserts into the halogen-carbon bond via an oxidative addition. The organonickel species transmetallates with Cr to form the organochromium(lll) nucleophile, which then reacts with the carbonyl compound. To make the process environmentally benign, a chromium-catalyzed version was developed where a chlorosilane was used as an additive to silylate the chromium alkoxide species in order to release the metal salt from the product. The released Cr is reduced to Cr with manganese powder. 

In the laboratory of G.A. Molander, a general route for the synthesis of eunicellin diterpenes was developed and was applied for the asymmetric total synthesis of deacetoxyalcyonin acetate. One of the key steps was an inramolecular NHK coupling reaction between an enol triflate and an aldehyde. The cyclopentenol product was formed in high yield as a 2 1 mixture of diastereomers. The undesired diastereomer could be transformed to the desired one using a Mitsunobu reaction. 

The Cl-Cl 9 fragment of (-)-mycalolide was assembled by J.S. Panek et al. via the NHK coupling between the C1-C6 vinyl iodide and C7-C19 aldehyde subunits. The desired allylic alcohol was obtained as a 1 1 mixture of stereoisomers and was oxidized to the corresponding ketone using Dess-Martin periodinane. The synthesis of the Cl-Cl 9 fragment was completed in three more steps. 

One of the key steps during the first total synthesis of (-)-aspinolide B by A. de Meijere and co-workers was the NHK reaction to form the ten membered lactone ring. The precursor for this key macrocyclization step was prepared by forming an ester from a three-carbon monoprotected diol fragment and a seven-carbon vinyl iodide fragment. Deprotection of the primary alcohol and its subsequent oxidation afforded the desired vinyl iodide aldehyde precursor. Exposure of this precursor to 15 equivalents of CrCl2 doped with 0.5% of NiCb at high dilution in DMF afforded the desired diastereomer in a 1.5 1 ratio. 

Cr-Ni bimetallic catalyst-promoted redox addition of vinyl halides to aldehydes. 

Transmetalation and then reduction by MciS OCrCl2 hydrolysis 

Kimura, K. Kuroda, T. Hiyama, T. Nozaki, H. Tetrahedron Lett. 1983, 24, 5281. Kazuhiko Takai was Prof. Nozaki s student during the discovery of the reaction and is a professor at Okayama University. 

Uenishi, J. Christ, W. J. Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644. Yo-shita Kishi at Harvard independently discovered the catalytic effect of nickel during his total synthesis of polytoxin. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 183, Springer-Verlag Berlin Heidelberg 2009 

Example 3, Intramolecular Nozaki-Hiyama-Kishi reaction  

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 196, Springer International Publishing Switzerland 2014 

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The multi-component procedure is also effective for the chromium-catalyzed addition of organic halides to aldehydes (the Nozaki-Hiyama-Kishi reaction) [73]. The active Cr(II) species is recycled by redox interaction with Mn powder as the stoichiometric co-reductant in the presence of MesSiCl (Scheme 34), which mainly liberates the chromium catalyst from the alkoxide adduct. The chemo- and diastereo-selective addition reaction is performed with a variety of organic halides and alkenyl triflates. In the case of crotyl bromide, the addition is highly stereoconvergent, i.e., the respective anti-... 

Grigg and coworkers developed bimetallic domino reactions such as the electro-chemically driven Pd/Cr Nozaki-Hiyama-Kishi reaction [69], the Pd/In Barbier-type allylation [70], Heck/Tsuji-Trost reaction/1,3 dipolar cycloaddition [71], the Heck reaction/metathesis [72], and several other processes [73-75]. A first example for an anion capture approach, which was performed on solid phase, is the reaction of 6/1-134 and 6/1-135 in the presence of CO and piperidine to give 6/1-136. Liberation from solid phase was achieved with HF, leading to 6/1-137 (Scheme 6/1.30) [76]. 

For a review encompassing the Nozaki-Hiyama-Kishi reaction, see Marshall, J. A. McNulty, L. M. Chemtracts 1997, 10, 50-52. 

The Nozaki-Hiyama Kishi reaction has been successfully utilized in the total synthesis of palytoxin (355) [170] brefeldin (356) [172], halichondrin B [173], brevetoxin [174], pinnatoxin A [174a] and others. The coupling of alkynyl iodides with aldehydes can be carried out smoothly using CrCl2 and 0.01% of NiCk... 

Chromium. Similar chlorosilane-mediated catalytic processes can be envisaged with many other early transition metals. The development of the first Nozaki-Hiyama-Kishi reactions catalyzed by chromium species [13] illustrates how to avoid the use of an excess of a physiologically suspect and rather expensive salt without compromising the efficiency, practicality and scope of the reaction. The tentative catalytic cycle is depicted in Scheme 3. 

Scheme 3. Proposed catalytic cycle for the first Nozaki-Hiyama-Kishi reactions catalyzed by chromium species.

For recent applications of this multicomponent system to other Nozaki-Hiyama-Kishi reactions catalytic in chromium see a) With acrolein acetals R. K. Boeckman, R. A. Hudack, J. Org. Chem. 1998, 63, 3524-3525 b) With trichloroethane J. R. Falek, D. K. Barma, C. Mioskowski, T. Sehlama, Tetrahedron Lett. 1999, 40, 2091-2094 e) CrC cat., TMSCl, NiClj cat., Al-powder M. Kuro-boshi, M. Tanaka, S. Kishimoto, K. Goto, H. Tanaka, S. Torii, Tetrahedron Lett. 1999,40,2785 - 2788. 

Many catalytic reactions are not sensitive to the presence of a sulfur atom on the substrate. Two examples can be quoted the Nozaki-Hiyama-Kishi reaction where a chlorosilane-mediated Cr-Mn-catalyzed C-C coupling occurs between a halogenoalkene and an aldehyde [63], and the [IrCl(CO)3]-catalyzed intramolecular allyl transfer in functionalized 1,3-thiozanes [64]. 

With substrates 82 and 137 in hand, the stage was set for the Nozaki-Hiyama-Kishi reaction it was performed using CrCli and 0.1% NiCh in dry DMSO. Under these mild and chemoselective conditions, a diastereomeric mixture of alcohols 138 was obtained in a 37% yield. Further optimization of these reaction conditions was not investigated due to the small quantity of substrate available. 

The total synthesis of the marine toxin polycavemoside A was achieved by J.D. White and co-workers. In order to couple the central pyran moiety in a Nozaki-Hiyama-Kishi reaction, the aldehyde side chain had to be first homologated to the corresponding terminal alkyne and subsequently transformed into a vinyl bromide. The aldehyde substrate was treated under the Ohira-Bestmann protocol, and the desired alkyne product was obtained in high yield. 

Related reactions Grignard reaction, Kagan-Molander samarium diiodide coupling, Nozaki-Hiyama-Kishi reaction ... 

Furstner, A., Shi, N. A Multicomponent Redox System Accounts for the First Nozaki-Hiyama-Kishi Reactions Catalytic in Chromium. J. Am. Chem. Soc. 1996, 118, 2533-2534. 

Bandini, M., Cozzi, P. G., Umani-Ronchi, A. The first catalytic enantioselective Nozaki-Hiyama-Kishi reaction. Polyhedron 2000, 19, 537-539. 

Durandetti, M., Nedelec, J.-Y., Perichon, J. An electrochemical coupling of organic halide with aldehydes, catalytic in chromium and nickel salts. The Nozaki-Hiyama-Kishi reaction. Org. Lett. 2001, 3, 2073-2076. 

Berkessel, A., Menche, D., Sklorz, C. A., Schroder, M., Paterson, I. A highly enantioselective catalyst for the asymmetric Nozaki-Hiyama-Kishi reaction of allylic and vinylic halides. Arrgew. Chem., Int, Ed, Engl, 2003,42,1032-1035. 

Alkylations. Using Cp2Cr as catalyst together with Mn and MejSiCl to induce the reaction of iodoarenes, iodoalkynes, allyl bromides, and enol triflates to aldehydes, secondary alcohols are formed. This process is a catalytic version of the Nozaki-Hiyama-Kishi reaction. Active Cr(II) catalyst can also be generated by Mn reduction of CpCrClj or CrClj. 

A catalytic variant of the Nozaki-Hiyama-Kishi reaction was recently introduced by Fiirstner [140]. The stoichiometric reaction generally requires at least three equivalents of chromium for the transformation to be complete. The large excess of CrCl2 and the toxicity of the chromium salts precludes the application of this reaction in industrial processes. The reaction developed by Fiirstner employs manganese powder and chlorotrimethylsilane to produce a catalytic cycle illustrated in Fig. 10-8 for the addition of vinyl iodides to aldehydes. The stereo-... 

Nozaki-Hiyama-Kishi Reaction (Organochromium Reagents)... 

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