Cycloisomerisation

Keywords Allylic substitution Catalysis Cross-coupling Cycloaddition Cycloisomerisation DNIC Ferrate Hydrogenase Iron... 

Transition metal catalysed cycloisomerisation of unsaturated systems is a powerful synthetic tool for the access of a wide range of heterocyclic and carbocyclic motifs [30], The use of NHCs as ligands for transition metal cycloisomerisation catalysts has been extensively studied [7],... 

For the last 2 decades ruthenium carbene complexes (Grubbs catalyst first generation 109 or second generation 110, Fig. 5.1) have been largely employed and studied in metathesis type reactions (see Chapter 3) [31]. However, in recent years, the benefits of NHC-Ru complexes as catalysts (or pre-catalysts) have expanded to the area of non-metathetical transformations such as cycloisomerisation. 

Allenes 111 undergo cycloisomerisation in presence of 20 mol% of catalyst 110 (Scheme 5.29) [32]. Interestingly, when the Grubbs first generation catalyst 109 is used in this reaction the ring-closing metathesis is observed [33]. 

A mixture of catalyst 110 and vinyl trimethylsilyl enolether 115 has been used in cycloisomerisation of (V-allyl-o-vinylanilines 114 and (V.A-diallyl-p-toluenesulfonamide 115 to afford the corresponding products 118 and 119, respectively (Scheme 5.30) [34]. It is believed that the active catalyst species is the ruthenium hydride NHC complex 117. 

Scheme 5.30 Cycloisomerisation of iV-aUyl-o-vmylamlines and iV,iV-diallyl-/ -toluenesulfonamide...

The same catalytic system mentioned above was also used in the synthesis of compound 121 (Scheme 5.31), which is a key intermediate in the total synthesis of fistulosin 122 [35], The catalyst 117 promoted the cycloisomerisation of the (V-vinylaniline 120 to indole ring 121 in 87% yield. 

Enynes 79 can also undergo cycloisomerisation reactions in presence of NHC/ transition metal complexes (Scheme 5.32). The cycloadduct 124 can be prepared either in presence of complex 110 [36] or in presence of a NHC-Ni complex (prepared in situ from a mixture of [ (COD) ] and IDTB 123 [37]). In the latter case, the active catalytic species is believed to be a Ni-H species that is generated via C-H activation of the carbene ligand. 

The use of the NHC-Ni catalytic system has also been used to promote the cycloisomerisation of vinyl cyclopropanes 125 to afford the cyclopentene rings 126 in excellent yields (Scheme 5.33) [38]. The reaction required only 1 mol% of [NiCCOD) ] and 2 mol% of IPr carbene. 

Vinyl cyclopropanes tethered to an aUcyne chain 127 were also subjected to the cycloisomerisation reaction in presence of the NHC-Ni catalyst system (Scheme 5.34) [39], The product formation depends on the substrate used and the NHC hgand. When SIPr carbene is used, three different products were obtained depending on the size of the R group attached to the alkyne moiety. If R is small (like a methyl) product 128 is obtained exclusively. If R is Et or Pr a mixture of 128 and 129 is obtained in 3 2 to 1 2 ratio, respectively. However, when R is large groups such as Bu or TMS only product 130 is obtained. When IfBu carbene 131 is used as the ligand, cycloisomerisation of 127 afforded product 128 exclusively, regardless of substituent size (Scheme 5.34) [39]. 

Aryl-substituted methylenecyclopropanes 132 can undergo intramolecular cycloisomerisation in catalytic presence of NHC-Pd complex 133 to form 1,2-dihydronaphthalenes 134 in moderate yields (Scheme 5.35) [40],... 

R = H, Me, MeO, PrO, MegN, Cl, F Scheme 5.35 NHC-Pd catalysed cycloisomerisation of aryl-substituted methylenecyclopropanes... 

Gold catalysts containing NHC ligands can also promote cycloisomerisation reactions. Bicyclo[3.1.0]hexanes 137-139 can be prepared from the cycloisomerisation of 1,5-enynes bearing a propargyUc acetate (135) in the presence of catalytic amounts of [AuCl(lPr)]/AgBF (Scheme 5.36) [41]. The cycloisomerisation reaction of 135 occurs by a 1,3-OAc shift/aUene-ene cyclisation/l,2-OAc shift sequence. Experimental results with allenyl acetate 136 support this hypothesis as 139 is obtained in higher ratios than 137 and 138 [41b],... 

Scheme 5.36 Golden catalysed cycloisomerisation of 1,5-enynes bearing a propargylic acetate...

Carbene/diphosphine platinum(ll) complexes 141 or carbene/monophosphine platinum(ll) complex 142 were shown to be efficient for the cycloisomerisation of 1,6-enynes 140 (Scheme 5.37) [42]. The product 143 is obtained in higher yields and higher enantioselectivity when catalyst 142 is employed rather than catalyst 141. 

Scheme 5.37 Enantioselective cycloisomerisation of 1,6-enynes catalysed by NHC-Pt complex...

Several new methods for the synthesis of the oxazole nucleus were published. A new consecutive three-component oxazole synthesis by an amidation-coupling-cycloisomerisation sequence was developed. The synthesis started from propargylamine 92 and acyl chlorides. To extend this process, a four component sequence involving a carbonylative arylation by substitution of one acyl chloride with an aryl iodide and a CO atmosphere was also performed <06CC4817>. 

Figurel.il Pd-catalysed cycloisomerisation ofdimethyl diallyl malonate. Kinetic profile based on H (MIVIR, and proposed reaction mechanism.

In the presence of copper(I) salts in acidic media o-ethynyl-benzaldehyde derivatives were found to cycloisomerise to 2-benzopyrylium salts (4.26.), The reaction, although working in the absence of catalyst too, was accelerated by the addition of different metal salts. The reaction was applied in the preparation of azaphilones and related molecules.30... 

The copper mediated cycloisomerisation of alkynyl imines provides a facile access to pyrroles and fused aromatic pyrroloheterocycles.50 In a recent example, shown in 8.39., the pyrrolopyrimidine bearing an acetylene moiety in the appropriate position cyclized smoothly to give the desired tricyclic compound in 89% yield.51... 

The mechanism of both the uncatalysed and W-catalysed cycloisomerisation of pent-4-yn-l-ol has been studied in detail. The endo reaction is complex but is favoured mainly as a result of stabilisation of a vinylidene intermediate <02JA4149>. The W-mediated cyclisation of alkynols has been used to synthesise glycals of the antibiotics vancosamine and saccharosamine <02OL749> and rrans-fused THP derivatives of 5 H-dibenzo[a,d]cycloheptene <02TL8697>. 

RCM has been used to effect the cycloisomerisation of allyl pent-2,3-dienyl ethers to dihydropyrans <06TL3971> and in the synthesis of the spiro[indolino-3,2 -pyran] 5 <06JOC2346>. 

A cycloisomerisation of the c -2,4-dienal 19 to 4,6,7,8-tetrahydro-3//-isochromene is promoted by Pd catalysts, whereas the Pt-catalysed reaction affords fused cyclopent-3-enones <06OL3153>. 

Competition between 5-exo-dig and 6-endo-dig cyclisation modes is observed in the Pd-catalysed cycloisomerisation of 2-alkynylbenzyl alcohols under neutral conditions. The formation of isochromenes through the latter mechanism is favoured by alkyl rather than aryl substitution at the triple bond terminus and also by low concentrations in a solvent of low polarity and higher reaction temperatures (Scheme 16) <03T6251>. 

The Cu-promoted enantioselective oxidative dearomatisation of aUcynylbenzaldehydes followed by a cycloisomerisation leads to azaphilones, fused 4//-pyrans (Scheme 1) <05JA9342>, while an alternative synthesis involves oxidation of a 1/7-benzopyrylium salt derived from a substituted benzaldehyde (Scheme 2) <05JOC4585>. Treatment of azaphilones with primary amines results in cleavage of the pyran ring and the formation of vinylogous y-pyridones. 

The Pd-catalysed cycloisomerisation of 2-(l -alkynyl)benzyl alcohol also leads to the isochromene and further elaboration of the 3-substituent resulted in a total synthesis of the fungal metabolite ( )-terreinol <05T 11882>. 

Copper-assisted cycloisomerisation of conjugated aUcynyl-imines gives pyrroles, even when the imine is actually the imine double bond of a pyridine. 

Conjugated enynes possess several of the same transition metal binding modes exhibited by their diyne counterparts, including Jt-coordination, a-carbenoid formation, and a/jt metal complexation (Scheme 35). In some cases, these constructs are very stable and can be isolated, but they are frequently transient structures in which the metal ion acts as a catalyst for enyne cycloisomerisation and ligand transformation reactions. 

Alkylidenecyclopropyl ketones 2, accessible by the Rh-catalysed cyclopropanation of allenes with a-diazo ketones, afford 4//-pyrans through a Pd-catalysed cycloisomerisation. In one instance, where the substrate lacked a hydrogen atom on the alkylidene moiety, a 2//-pyran was obtained <04JA9645>. 

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