Nicholas reactions

The Nicholas reaction enables efficient substitution reactions of propargyl alcohols, ethers, and acetates. Prior to the substitution step, dicobalt octacarbonyl reacts with the alkyne to yield cobalt-alkyne complex 1. The resulting organometallic complex reacts with inter- or intramolecular nucleophiles in the presence of a Lewis or protic acid to furnish desired substitution products 2. The cobalt-complexed alkyne can be oxidatively removed after this step or used to further fiinctionalize the Nicholas reaction products. The stereoselective synthesis of chiral products using the title reaction is also possible.  

Nicholas continued his study of these propargylic substitution 

The mechanism of the Nicholas reaction is best described as an SnI process. Protonation of the alcohol in 4 followed by loss of water from cation 8 yields cobalt-stabilized carbocation 5. Friedel-Crafts reaction of this electrophile with anisole provides resonance-stabilized carbocation 9 which, upon removal of a proton, furnishes the substitution product 6. In addition to electron rich aromatics like anisole, a variety of neutral carbo- and heterocyclic nucleophiles react successfully with the carbocation 

Stabilization of adjacent carbocations can be depicted by several resonance structures (5, 10-12) which highlight opportunities for charge delocalization. Early NMR and IR studies by Nicholas on the isolable tetrafluoroborate salt of 5 and several analogs demonstrated measurable loss of electron density at cobalt (versus alcohol 4), thus implicating structures like 10 and 12 in the stabilization of the positive charge. Furthermore, Melikyan obtained an X-ray crystal structure of a carbocation stabilized by two adjacent cobalt-complexed alkynes that showed shortening of one cobalt a-carbon distance like that shown in compound 12.  

Modifications to the standard Nicholas reaction generally fall into the following categories asymmetric reactions, use of heteroatom nucleophiles, use of metals other than cobalt, reactions of neutral electrophiles, reactions of carbocations not in the a-position, cycloadditions, and rearrangements. 

Jacobi, P. A. Zheng, W. In Enantiosel. Synth. p-Amino Acids Juaristi, E., ed. Wiley-VCH New York, N. Y., 1997, 359. 

Hexacarbonyldicobalt-stabilized propargyl cation is captured by a nucleophile. Subsequent oxidative demetallation then gives propargylated product. 

Example 2, intramolecular Nicholas reaction using chromium  

R ctiy of C02(CO),.st.bilizod propa, lic calon, mlh nucleophll.s (NIdiolas,, 977)  

The Nicholas reaction was used to synthesize the p-lactam precursor of thienamycin in the laboratory of P.A. Jacobi and thereby accomplish its formal total synthesis. The necessary p-amino acid was prepared by the condensation of a boron enolate (derived from an acylated oxazolidinone) with the cobalt complex of an enantiopure propargylic ether. The resulting adduct was oxidized with ceric ammonium nitrate (CAN) to remove the cobalt protecting group from the triple bond, and the product was obtained with a 17 1 anti.syn selectivity and in good yield. 

The total syntheses of (+)-secosyrins 1 and 2 was achieved and their relative and absolute stereochemistry was unambiguously established by C. Mukai and co-workers. To construct the spiro skeleton of these natural products, the intramolecular Nicholas reaction was utilized. The alkyne substrate was first converted to the dicobalt hexacarbonyl complex by treatment with Co2(CO)8 in ether. Exposure of the resulting complex to boron trifluoride etherate at room temperature brought about the ring closure with inversion of configuration at C5 to afford the expected tetrahydrofuran derivative. The minor product was the C5 epimer which was formed only in 15% yield. 

The application of the intramolecular Nicholas reaction by C. Mukai et al. made it possible to develop a novel procedure for the construction of oxocane derivatives. Interestingly, several Lewis and Bronsted acids gave rise to complex mixtures. However, the use of mesyl chloride/triethylamine in refluxing DCM afforded the desired oxocane as the sole product. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 180, Springer-Verlag Berlin Heidelberg 2009 

Nicholas reaction. In Name Reactions for Homologations-Part / Li, J. J., Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2009, pp 284-298. (Review). 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 193, Springer International Publishing Switzerland 2014 

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Not surprisingly, the cobalt-complexed ether products obtained by the Nicholas reaction can be subjected directly to the Pauson-Khand sequence (Scheme 7).244... 

Metal-catalyzed substitution reactions involving propargylic derivatives have not been studied in much detail until recently [311, 312]. In this context, the ability shown by transition-metal allenylidenes to undergo nucleophilic additions at the Cy atom of the cumulenic chain has allowed the development of efficient catalytic processes for the direct substitution of the hydroxyl group in propargylic alcohols [313]. These transformations represent an appealing alternative to the well-known and extensively investigated Nicholas reaction, in which stoichiometric amounts of [Co2(CO)g] are employed [314-317]. 

The dicobalt octacarbonyl-promoted Nicholas reaction has been used in the preparation of polycyclic ethers related to the marine polyethers ciguatoxin 32 and gambiertoxin <1999JOC37>. 

Interestingly, seven-membered conjugated diyne complex 16 is produced by the acid-promoted Nicholas reaction of the dicobalt-coordinated bispropargylic complex (Equation (7)). The cyclization proceeds via an intramolecular coupling reaction between a propargyiic cation and an alkene produced after dehydration. The molecular structure of seven-membered diyne complex 16 is confirmed by X-ray analysis, although the decomplexation is not successfully carried out. 

Combinatorial chemistry and solid-phase synthesis have evolved in the last decade to become one of the most important techniques to save time for drug discovery. To reach its full potential, the solid-phase synthesis has to incorporate many versatile organometallic reactions developed over recent several decades. The first example of the Nicholas reaction on solid phase was reported by Kann and his co-workers in 2002, which involves the reaction of polymer-bound cobalt complexes 51 with various carbon-centered nucleophiles in the presence of a Lewis acid to... 

Schreiber and co-workers provide one of the most stylish examples of this approach. The successful synthesis of (T)-epoxydictymene relies on selective activation of an ethoxy group compared with an allyloxy group in the Nicholas reaction (selectivity 8.5 1) and the stereoselective PKR (Equation (37)). ... 

Coordination to alkynes distorts the triple bond character nearer to that of a double bond, decreasing the linearity. Utilization of the coordination effect makes it feasible to prepare cyclic alkynes whose synthesis is difficult to achieve. Highly strained cyclooctyne can be prepared by coordination. As an example, starting from (R)-pulegone, three of the four rings of the epoxydictymene skeleton 152 were constructed by the consecutive Lewis acid-promoted Nicholas reaction of allylic silane 149 to form 150, and the intramolecular Pauson-Khand reaction of 151. The total synthesis of (+)-epoxydictymene 153 from 152 has been achieved [38]. 

The seven-membered cyclic ether 161 containing the Co-stablized triple bond was prepared by the Nicholas reaction of 160. The decomplexation and reduction of the triple bond to the double bond to produce 162 were achieved by Rh-catalysed hydrogenation. The method was used for the preparation of the A/B fragment of ciguatoxin [41]. 

Complexation of an alkyne to dicobalthexacarbonyl is a well-known way to stabilize carbocationic charges generated in the carbon a to the alkyne. These carbocations react with different nucleophiles. This process, the Nicholas reaction [112], has been used to generate enynes that undergo, in a domino fashion, a PKR. 

Later on, Schreiber used consecutively these two reactions in the key step for the synthesis of diterpene (-i-)-epoxydictimene (73), starting from natural (R)-pulegone [116,117]. This approach was built on their preliminary studies on Lewis acid mediated intermolecular Nicholas reactions [118]. They prepared functionalized enyne 70 bearing a mixed acetal. This compound was transformed into its dicobalt-hexacarbonyl complex and, in the presence of a carefully selected Lewis acid, it formed a stabilized carbocation by release of the more accessible ethyl moiety. This cation reacted intramolecularly with the allylsilane giving the central eight membered ring of the natural product... 

For a recent review on the Nicholas reaction see Teobald BJ (2002) Tetrahedron... 

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