Cyclooctyne preparation

Apparatus 1-1 round-bottomed, three-necked flask with a dropping funnel, a mechanical stirrer and a thermometer, combined with a vent, for the addition of bromine and the dehydrobromination to 1-bromocyclooctene 1-1 flask (see Fig. 1) for the preparation of cyclooctyne. 

The only other report (88) of a gold(I) acetylene complex concerns [AuBr(cyclooctyne)2], which was prepared from aurous bromide and cy-clooctyne. 

The acyclic diyne metathesis polymerization of dodeca-2,10-diyne is catalysed by W(=CEt)(OCMe3)3 see equation 73. But-2-yne is eliminated and the product is an off-white insoluble powder with the same Tm as the polymer prepared from cyclooctyne (Section XII.B)7. 

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]. 

Alkyncs can be prepared through the use of two basic procedures. Before these procedures are presented, it should be noted (hat the smallest ring in which an acetylene linkage is stable at room temperature for an extended period of time is cyclooctyne. 

In the attempted preparation of cyclooctyne (14)10) from 1-chlorocyclooctene (12) using lithium piperidide as a base only l-(piperidyl)-cis-cyclooctene (13) was obtained 10). This result was interpreted by assuming (14) as an intermediate which then adds lithium piperidide to yield (13). 

Cyclooctyne (14) adds bromine to give l,2-dibromo-cis-cyclooctene93) this is presently the only route to prepare a pure 1,2-dihalocyclooctene. The addition of bromine and iodine to (31) leads to the unexpected products (54) apparently trans-annular attack of the cationic intermediate (55) by the nucleophilic sulfur produces a strained sulfonium ion which stabilizes itself by ring opening to (54)201). 

The method has now been extended to preparation ot ci s-cycIooctenyne-3 (equation II) and 5-substituted cyclooctynes (equation III) ... 

An additional advantage of the intramolecular protocol stems from the opportunity to prepare easily the required polyfunctional precursors via cobalt carbonyl stabilized propargyl cations. The approach based on the tandem utilization of Co-mediated alkylation and Pauson-Khand annulation was developed in Schreiber s studies to elaborate short pathways for the synthesis of polycyclic compounds. An example of the efficiency of this protocol is the two-step transformation of the acyclic precursor 409 into the tricyclic derivative 410. The cobalt-complexed acetal 409 was first transformed into the cyclooctyne derivative 411 via intramolecular reaction of the in situ generated propargyl cation 409a with the allylsilane moiety. Cyclooctyne 411 underwent smooth cycloaddition in the presence of carbon monoxide to give the target compound 410 with excellent stereoselectivity. 

Cyclooctyne (75) can be prepared according to the usual rhethods of synthesis of acetylenic compounds. For instance, oxidation of the bishydrazone of cyclooctane-1,2-dione (74) " " or debromination of 1,2-dibromocyclooctene (76) with magnesium or the photolysis of the anion of I-tosyIamino-1,2,3-triazole derivative (77) gave cyclooctyne (75). 

Dihydrazones can be oxidized to alkynes with O2 (CuCl as a catalyst), HgO, ° " FsCCOaAg and Pb(OAc)4 (Scheme 61). 1-Amino-1,2,3-triazoles, which are sometimes observed as by-products in the HgO oxidation of 1,2-dihydrazones, can be oxidized with Pb(OAc)4 to give alkynes. Cyclooctyne" has been prepared and cycloheptyne and cyclohexyne" have been generated by this method (Scheme 62). The 1-tosylamino-1,2,3-triazoles can also be used as educts for alkyne synthesis the anions are decomposed to yield the corresponding alkyne, N2 and toluenesulfmate (Scheme 63). ... 

Taking in account the composition of the commercial mixture 45 + 46 (35% cis, 65% trans), of the anti addition of Br2, of the structure of 50 and 49 as well as their formation ratio, we can say that the first eliminations of H-Br are anti. Thus the second eliminations of H—Br have to be anti from 50 and syn from 49. Comparative experiments showed that r-BuONa alone and less efficiently NaNH2 alone in THF are able to give the anti-eliminations but not the syn ones. On the contrary, NaNH2-f-BuONa in the same solvent is able to perform all the reactions. The side reaction with complex base is still isomerization of 51 to 52. An application of this study was the preparation of cyclooctyne with 30—35% yield35. ... 

In a newer preparation of cyclooctyne from 1-bromocyclooctene, Wittig and Dorsch1 isolated the product as the crystalline 2 1 complex with silver nitrate in... 

Adducts of the marginally stable cyclooctyne and cyclooctenyne with the Pt[PPh3l2 [48] and - Co2(CO)5 [49, 50] fragments have been prepared by direct complexation. Reaction of 1,2-dibromocycloalkenes with sodium amalgam in the presence of Pt(PPh3)3 has produced complexes 27-29 of the unisolable cycloheptyne, cyclohexyne [51], and even cyclopentyne [47] (Scheme 4-10) the free alkynes apparently are not intermediates in these reactions. 

As a specific example of such syntheses, the preparation of [6]-3,6-oxepinophane starting from furan and cyclooctyne <87CB769> should be noted. The formation of 2,7-diethyl-3,4,5,6-tris(trifluoromethyl)oxepin from 2,5-diethyl-3,4-di(trifluoromethyl)furan and di(trifluoromethyl) ethyne is also of interest <92JHC1 13>. 

The mechanism of CO substitution with phosphines in the 19-e complex Cp Mn(CO)2NO is dissociative, followed by spontaneous oxidation of the product. Trinuclear clusters containing CpRe(CO)-fiagments in combination with iron carbonyl sulfido dimers have been reported. The synthesis of CpMn(CO)2(n -cyclooctyne) and the ligand rearrangement to an allene complex within the metal coordination sphere has been investigated by NMR spectroscopy. Tc labelled esters of cytectrene carboxylic acid have been prepared by exchange with ferrocenylcarboxylic acids in the presence of carbonyl donors. ... 

The successful preparation of cycloalkynes also opened up the possibility to explore their unique chemical reactivity. In fact, the transient existence of the cycloalkyne species could initially only be indirectly corroborated by fast in situ trapping of the smaller-sized rings (seven carbons and below) before decomposition [31]. While not strictly applicable to cyclooctyne, which is the smallest cyclic alkyne that can be isolated and stored in pure form, Blomquist already noted that nevertheless careful exclusion of air was requisite to avoid rapid decomposition. More importantly, he was also the first to observe that cyclooctyne reacts explosively when treated with phenyl azide, forming a viscous liquid product [8]. This remark is in fact the first historic administration of a process that has now become known as strain-promoted azide-alkyne cycloaddition (SPAAC). 

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