Nicholas reaction, intramolecular

Example 2, intramolecular Nicholas reaction using chromium ... 

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. 

Crisostomo, F. R. P., Martin, T., Martin, V. S. Stereoselective intramolecular Nicholas reaction using epoxides as nucleophiles. Org. Lett. 2004, 6, 565-568. 

One of Green s many applications of the chemistry of cobalt-alkyne complexes in synthesis involved formation of a seven-membered ring via an endocyclic intramolecular Nicholas reaction. The key step in his successful synthesis of allocolchicine NSC 51046 (38) was production of cyclic cobalt-alkyne complex 37 from reaction of acetate 36 and boron trifluoride. Hydrosilylation of the organometallic complex followed by desilylation yielded the corresponding alkene that was ultimately transformed into the target tricycle. ... 

Bertrand recently generated six- and seven-membered rings using a terminal alkene nucleophile in exocyclic intramolecular Nicholas reactions. Depending on the nature of the Lewis acid, the carbocation intermediate formed upon cyclization (e.g., 46) could be converted into a halide, amide, ester, or alkene. For example, alcohol 45 undergoes a 6-e [Pg.293]

Several reports describe a tandem intermolecular Nicholas/intramolecular Nicholas reaction sequence for the synthesis of cyclic compounds. Green employed this strategy for the synthesis of indolophanetetrayne cobalt complexes. Dimerization of substituted indole 50 with boron trifluoride furnishes target 51 in 55% yield. Green also prepared a cobalt-complexed cycloheptyne via tandem intermolecular Nicholas/intramolecular Nicholas reactions. Boron trifluoride promotes combination of cobalt-alkyne complex 52 with allyltrimethylsilane to first yield intermolecular product 53 and then the desired intramolecular product 54. ... 

Tyrrell demonstrated a three step tandem sequence involving an intermolecular Nicholas reaction, intramolecular Nicholas reaction, and a cationic cyclization. Treatment of silyl enol ether 55 with hexacarbonyl(propiolaldehyde diethyl acetal) dicobalt and boron trifluoride provides cobalt-alkyne complex 56. Exposure of this material to tetrafluoroboric acid promotes an intramolecular Nicholas reaction to form the second six-membered ring. Alkyne decomplexation with ceric ammonium nitrate enables the final cyclization step to yield the target tricycle 57." ... 

The most impressive use of a tandem strategy involving the Nicholas reaction in a total synthesis project is Schreiber s preparation of (+)-epoxydict5miene (61). Cobalt complexation of 58 followed by an endocyclic intramolecular Nicholas reaction with an allylsilane nucleophile yields Pauson-Khand precursor 59. Treatment of 59 with iV-methylmorpholine-iV-oxide (NMO) promotes the Pauson-Khand reaction to furnish tetracycle 60 which was ultimately converted to the target natural product 61. ... 

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. 

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]. 

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... 

Intramolecular alkylation reactions employing allylsilanes have been developed. A taxoid bicyclo[9.3. l]pentadecane ring system was prepared via intramolecular alkylation of (150). It is interesting to note that the alkylation occurred in the y-position relative to the alkyne (Scheme 218). A Nicholas reaction was used in the synthesis of (+)-epoxydictymene (Scheme 219). 

Intramolecular delivery of the alkynyl moiety in ion pair 24 or -chloride 25 via the Zn tether would lead stereo selectively to a-C-glycosyl compound 17. The Nicholas reaction [35] with triflic acid-induced isomerization [36] of the dicobaltohexacarbonyl complex of aUcyne 17 provides cleanly the corresponding /3-C-glucoside complex 18 (O Scheme 4). Decomplexation with iodine and acetylation then gives /3-C-disaccharide 19. 

Nicholas reaction. The intramolecular version has been applied to the synthesis of benzopyran system. ... 

Several transition metal mediated processes rely on the participation of Lewis acids, among these, the Nicholas reaction figures prominently. After treatment with BF3-Et20, Co2(CO)6 complexed propargylic alcohols provide the carbocation, which can be trapped intramolecularly with various nucleophiles including epoxides (eq 55), or via hydride transfer from an appropriately poised benzyl moiety (eq 56) or aromatic rings. In the latter case, access to the relatively small [7] metacyclophane derivatives was possible. 

An underused property of cobalt-coordinated alkynes is the stabilization of propargyllic cations. The Nicholas reaction is a propargylic substitution reaction facilitated by the ability of the adjacent cobalt complex to stabilize the propargylic cation, 67 to 68. Both carbon and heteroatom nucleophiles have been used to effect this transformation. " This transformation has been been used as a strategy to introduce the alkene component for an intramolecular PKR. Shea has probed the use of an... 

The Nicholas and Pauson-Khand reactions, as well as the bond-angle effect, have been combined in a single synthetic scheme to make more efficient use of the cobalt. This has been done in a synthesis of epoxydictamine 7.90 (Scheme 7.24)." The Nicholas reaction was employed, in which a carbocation 7.87, generated from acetal 7.86, was trapped by an allylsilane nucleophile intramolecularly, to form the eight-membered ring... 

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. ... 

Since its discovery just over thirty years ago, the Nicholas reaction has become a highly useful tool for the organic chemistry community. Applications of the Nicholas reaction fall into four categories intermolecular reactions, endocyclic intramolecular reactions, exocyclic intramolecular reactions, and tandem reactions. For this discussion, endocyclic means that the cobalt-complexed alkyne is in the ring formed during the Nicholas reaction, while exocyclic indicates that the cobalt-alkyne complex is outside the newly generated ring. 

In addition to her studies on the asymmetric Nicholas reaction mentioned previously (13 14), Tyrrell investigated standard intramolecular cyclizations to generate benzopyrans. An important advance in this report is that Tyrrell performed the cobalt complexation, Nicholas reaction, and cobalt decomplexation using a one-pot procedure. The conversion of propargyl alcohol 48 into benzopyran 49 highlights this strategy... 

The Nicholas reaction [103] has been successfully exploited for a novel glyco-sylation reaction based on the internal delivery concept (Scheme 31a). The suitably O-protected glycop3rranoside derivative 111 bearing the cobalt-complexed 4-alkoxy-6-phenyl-5-hexynoate residue at the anomeric position affords the corresponding propynyl cation 112 under Lewis acid catalysis. The intermediate 112 collapses spontaneously to form the oxoniiun ion delivering the cobalt-complexed y-lactone 113. The oxocarbenium cation is then intramolecularly captured by its counter alkoxy anion leading to glycoside 114. 

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