Diynes 2 + 2 + 2-cycloaddition

The methodology is useful for a variety of synthetic purposes. The cycloadditions are not subject to steric hindrance. Thus diyne cycloadditions to 2,5-disubstituted furans or pyrroles, followed by elimination of the oxygen or nitrogen bridges, provides an excellent, short route to peri-substituted arenes, as in the following examples 4 6 8... 

Tsuda, T., Transition Metal Catalyzed Diyne Cycloaddition Copolymerization , in The Polymeric Materials Encyclopedia, CRC Press, Boca Raton, Vol. 3, pp. 1905-1915. 

A simple synthesis of dihydrobenzo[c]furans was recently reported by Yus by starting from the lithiation reactions of 4-heterosubstituted dibenzothiins <03T2083>. Another way in which dihydrobenzo[c]furans can be prepared was recorded by Cheng who made use of a CoI fPPhjlj/Zn catalyzed [2+2+2] ene-diyne cycloaddition of 1,6-heptadiynes with allenes as illustrated telow. It was shown that these conversions were highly regio- and chemoselective. <03CC718>. 

Hsiao, T.-S., Santhosh, K.C., Liou, K.-E, and Cheng, C.-H., Nickel-promoted first ene-diyne cycloaddition reaction on synthesis and photochemistry of the fullerene derivatives, /. Am. Chem. Soc., 120, 12232, 1998. 

The addition of 1,3-dipoles to alka-l,3-diynes has been studied in less detail than that to conjugated alkadienes and alkenynes (80UK1801). Conjugated diynes get involved in [2- -3]cycloaddition at the unsubstituted acetylene bond. 

The total synthesis of ( )-estrone [( )-1 ] by Vollhardt et al. is a novel extension of transition metal mediated alkyne cyclotrimeriza-tion technology. This remarkable total synthesis is achieved in only five steps from 2-methylcyclopentenone (19) in an overall yield of 22%. The most striking maneuver in this synthesis is, of course, the construction of tetracycle 13 from the comparatively simple diyne 16 by combining cobalt-mediated and ort/io-quinodimethane cycloaddition reactions. This achievement bodes well for future applications of this chemistry to the total synthesis of other natural products. 

A subsidiary approach involves nuclear modification of the arylsilanes so obtained. The requisite organometallics can be prepared from aryl halides, or by deprotonation of a suitably activated (c.g. methoxy-substituted) arene. A more specialized route involves cycloaddition between alkynylsilanes and diynes. 

Aryl- and alkenylcarbene complexes are known to react with alkynes through a [3C+2S+1C0] cycloaddition reaction to produce benzannulated compounds. This reaction, known as the Dotz reaction , is widely reviewed in Chap. Chromium-Templated Benzannulation Reactions , p. 123 of this book. However, simple alkyl-substituted carbene complexes react with excess of an alkyne (or with diynes) to produce a different benzannulated product which incorporates in its structure two molecules of the alkyne, a carbon monoxide ligand and the carbene carbon [128]. As referred to before, this [2S+2SH-1C+1C0] cycloaddition reaction can be carried out with diyne derivatives, showing these reactions give better yields than the corresponding intermolecular version (Scheme 80). 

The [2-I-2-I-2] cycloaddition reaction of diynes 40 and carbon dioxide 41 were successfully catalysed by a NHC-nickel (Scheme 5.12) [15]. The NHC-Ni complex was prepared in situ from [NiCCOD) ] and two equivalents of carbene. Pyrones 42 were obtained in excellent yields at atmospheric pressure of CO and mild reaction conditions. 

Scheme 5.12 [2-I-2-I-2] Cycloaddition reactions of diynes and CO catalysed by NHC-Ni complex...

Pyridine compounds 45 can also be produced by the NHC-Ni catalysed cycloaddition between nitriles 43 and diynes 44 (Scheme 5.13) [16]. The SIPr carbene was found to be the best ligand for the nickel complex in this reaction. The reaction required mild reaction conditions and low catalyst loadings, as in the case of cycloaddition of carbon dioxide. In addition to tethered aUcynes (i.e. diynes), pyridines were prepared from a 3-component coupling reaction with 43 and 3-hexyne 23 (Scheme 5.13). The reaction of diynes 44 and nitriles 43 was also catalysed by a combination of [Ni(COD)J, NHC salts and "BuLi, which generates the NHC-Ni catalyst in situ. The pyridines 45 were obtained with comparable... 

The NHC-nickel catalytic system is also useful in the synthesis of pyridones 48. The [2h-2h-2] cycloaddition of diynes 44 and isocyanates 47 affords a wide range of pyridones 48 in excellent yields in presence of [Ni(COD)2]/SIPr catalytic system (Scheme 5.14) [18]. 

Scheme 5.14 [2+2+2] Cycloaddition of diynes and isocyanates in presence of [Ni(COD) ]/SIPr catalytic system...

A plausible mechanism for the [2+2+2] cycloaddition reactions between diynes and heterocumnlenes (or nitriles) is shown in Scheme 5.16. Initially [2+2] oxidative addition of one alkyne and the heterocnmnlene (or nitrile) forms the five-mem-bered intermediate 54 compound 55 is formed after the insertion of the second alkyne and finally the seven-membered compound 55 undergoes reductive elimination to afford the prodnct 56 and regenerate the Ni(0) catalyst. 

Scheme 5.16 Plausible mechanism for the [2+2+2] cycloaddition reactions between diynes and heterocumnlenes...

It is not quite clear which step takes place first - the Co-catalyzed [2+2+1] cycloaddition of the outer alkyne moiety, or the Diels-Alder reaction of the diene with the inner alkyne to form a 1,4-cyclohexadiene, which then undergoes a Pauson-Khand reaction with the remaining alkyne. Recently, it has been shown that a domino reaction can also be performed using 1 mol of a 1,7-diphenyl-1,6-diyne 6/4-20 and a 1,3-diene 6/4-21 in the presence of Co/C at 150 °C under 30 atm CO, to give the polycyclic compounds 6/4-22 as sole product (Scheme 6/4.7) [282]. 

Rather complex structures are obtained by a novel chromium(O)-mediated three-component domino [6jt+2jt] cycloaddition described by Rigby and coworkers [315]. Irradiation of a mixture of the chromium complex 6/4-134 and the tethered diyne 6/4-135 with a Pyrex filter at 0 °C gave the polycyclic compounds 6/4-136 in medium to good yield (Scheme 6/4.34). 

Ruthenium(ll)-catalyzed cycloadditions of diynes with bicycloalkenes illustrate the synthetic importance of ruthena-cyclopentatrienes as biscarbenoid intermediates.380 Reaction of 1,6-diyne 448 and biscyclic alkene 449 with ruthenium catalyst afforded a mixture of biscyclopropanation product 450 and cyclotrimerization product 451 (Scheme 113). 

Itoh and co-workers reported the ruthenium(n)-catalyzed [2 + 2 + 2]-cycloaddition of 1,6-diynes with isocyanates to afford the corresponding bicyclic pyridones 163 (Scheme 72).356 357 For previously reported ruthenium-catalyzed [2 + 2 + 2]-cycloaddition of 1,6-diynes see Refs 358 and 358a, and for theoretical calculations of the cyclocotrimer-ization of alkynes with isocyanates, isothiocyanates, and carbon disulfide see Refs 359 and 359a. 

Based on this work, Itoh and co-workers developed ruthenium(n)-catalyzed [2 + 2 + 2]-cyclotrimerizations of 1,6-diynes 174 and electron-deficient nitriles (Equation (34)),368>368a These partially intramolecular cycloadditions proceed through ruthenacycle intermediates as well. The importance of using electronically activated nitriles is underlined by the fact that acetonitrile and benzonitrile gave only very low yields. 

For a related example of a ruthenium(II)-catalyzed cycloaddition of 1,6-diynes with isothiocyanates and carbon disulfide, see Yamamoto, Y. Takagishi, H. Itoh, K. J. Am. Chem. Soc. 2002, 124, 28-29. 

Itoh and coworkers111 carried out tandem [2 + 2 + 2]/[4 + 2] cycloadditions catalyzed by a ruthenium catalyst. The reaction of diyne 147 with excess norbomene 148 in the presence of ruthenium catalyst 153, for example, afforded 149. Adduct 150 either dissociated from the catalyst or reacted with another equivalent of norbornene. In the latter case, a ruthenium catalyzed Diels-Alder reaction occurred, affording hexacyclic adduct 152 via 151 (equation 43). Compounds 150 and 152 were obtained in yields of 78% and 10%, respectively. Both cycloaddition reactions proceeded with complete stereoselectivity. When 1,6-heptadiyne was used instead of 147, only trace amounts of a cycloadduct were obtained. Replacing norbornene by norbornadiene, which was expected to result in polymer formation, did not afford any adduct at all. 

The cobalt mediated [2 + 2 + 2] cycloadditions of a, >-diynes with indole were only accomplished when the nitrogen atom was substituted with an electron-withdrawing... 

Vollhardt and colleagues338b studied the regiochemistry in these cycloaddition reactions. When the a,cu-diynes had large substituents at both termini, the reaction with W-phenylsulfonylindole did not afford any adduct due to steric hindrance. When smaller substituents were present, the cycloaddition proceeded in such a way that the larger substituent was distant from the phenylsulfonamide moiety, as illustrated for the reaction of 585 with 586 (equation 168). Anti 587 and syn 588 were obtained in a 61 39 ratio. 

Tsuda and coworkers350 used nickel(O) complexes to effect the [2 + 2 + 2] cycloadditions between two alkyne units and one alkene unit and employed this strategy to synthesize copolymers. Thus, the reaction of diyne 602 with A-octylmaleimide (603) catalyzed by Ni(CO)2(PPh3)2 afforded copolymer 604 with a maximum yield of 60% and a GPC molecular weight of as high as 35,000, which corresponds to n = 64 (equation 172). The exo,exo-bicyclo[2.2.2]oct-7-ene moiety of 604 arises through the reaction of the initially formed [2 + 2 + 2] adduct with another equivalent of A-octylmaleimide. 

Ikeda and coworkers351 performed [2 + 2 + 2] cycloadditions of diynes with a,ji-enones using NiCl2/Zn (1 10) as the catalytic couple. In these reactions, nickel dichloride... 

Rothwell and colleagues352 studied the titanium mediated [2 + 2 + 2] cycloaddition of alkenes with monoynes and diynes. Among the reactions studied, the reaction between styrene (29) and diyne 609 in the presence of titanium catalyst 610 proved cleanest (equation 175). The reaction yielded 614 via a [2 + 2 + 2] cycloaddition followed by a titanium mediated suprafacial [1,5] H-shift involving 611-613. The cis relationship between the trimethylsilyl group and the phenyl group indicated that the initially formed titananorbornene 611 had an endo stereochemistry. 

Kotha and Brahmachary353 prepared some constrained a-amino acids using a rhodium mediated [2 + 2 + 2] cycloaddition reaction. The indane type of a-amino acids were synthesized by reacting diynes with monoynes using Wilkinson s catalyst354. Thus, the reaction of diyne 615 with 616 afforded a-amino acid derivative 617 (equation 176). 

In the intermolecular reaction of tetraynes, where two 1,6-diyne moieties were directly connected, with monoalkynes, CHIRAPHOS (2,3-bis(diphenylphosphino) butane) was the choice of chiral ligand, and axial chirality was enantiomericaUy generated between the formed benzene rings (Scheme 11.17). Hexaynes with a 1,3-diyne moiety also underwent an intramolecular [2-i-2-i-2] cycloaddition, and the Ir-xylylBINAP (2,2 -bis[di(3,5-xylyl)phosphino]-l,l -binaphthyl) catalyst induced an excellent enantiomeric excess (ee) (Scheme 11.18) [24]. 

Regioselective syntheses of 1,3,5-unsymmetrically substituted benzenes (309) are catalyzed by Pd(dba)2/PPh3 mixed alkyne/diyne reactants give mixtures containing homocoupled and mixed products (24 21 from HC CPh + HC=CC= CC Hn). The probable mechanism involves oxidative addition to the Pd(0) center, insertion of the second diyne into the Pd—H bond, reductive coupling and subsequent jr-complexation of this product to Pd(0), followed by Diels-Alder cycloaddition of the third diyne and elimination of product. 

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