Hydride transfer 1,5-, cascade

Mechanistically, the Brpnsted acid-catalyzed cascade hydrogenation of quinolines presumably proceeds via the formation of quinolinium ion 56 and subsequent 1,4-hydride addition (step 1) to afford enamine 57. Protonation (step 2) of the latter (57) followed by 1,2-hydride addition (step 3) to the intermediate iminium ion 58 yields tetrahydroquinolines 59 (Scheme 21). In the case of 2-substituted precursors enantioselectivity is induced by an asymmetric hydride transfer (step 3), whereas for 3-substituted ones asymmetric induction is achieved by an enantioselective proton transfer (step 2). 

The Kim group envisioned that the saturated aldehydes 19 might also be used as viable substrates for asymmetrie [l,5]-hydride transfer/cyelization reactions by coupling the in situ generation of the o,p-unsaturated imin-ium intermediate 22 by oxidation (Seheme 4.11a). IBX (2.0 equiv.) was found to be the suitable organie oxidant compatible with the established catalytic system (20 mol% of C3 and 20 mol% of DNBS) for the asymmetric [l,5]-hydride transfer reactions. This novel cascade reaction also allows the efficient synthesis of ring-fused tetrahydroquinoline products with high enantioseleetivity. 

According to the proposed mechanism (Scheme 6.20), the first step of this cascade reaction is protonation of the substituted pyridine by CPA to generate the pyridinium salt 51. Then, the reduction of 51 by 1,4-hydride transfer from the Hantzsch ester gives the enamine intermediate 52, which isomeri-zes to iminium 53 in the presence of CPA. The subsequent AFC reaction will afford the desired product and release the chiral phosphoric acid. 

Cobalt(II) complexes with the chiral AA -dioxides (140a,b) have been reported to catalyse the cascade 1,5-hydride transfer and cyclization of (144) to afford tetrahy-droquinolines (145) in <90% ee. A plausible mechanism was proposed to account for the origin of the activation and asymmetric induction. a,/3-Enones decorated with the pyridine A-oxide chelating unit (146) have been shown to undergo a Michael addition of malonates, catalysed by a complex generated from (TfO)2Zn and the bisoxazoline ligand (147) with <96% ee ... 

Scheme 3 Cascade [l,5]-hydride transfer/dn-electrocyclic ring closure 2.2 Reactivity of Different Hydrogen Donors...

For a long time, harsh thermal conditions were always needed to overcome the high energy barrier of [l,5]-hydride transfer, which severely limited the application of this strategy. Seidel et al. employed Ga(OTf)3 to catalyze the cascade process of 8, via which tetrahydroquinolines 9 could be furnished in 90 % yield within 15 min at room temperature (Scheme 5) [89]. Meanwhile, the chiral bisoxazoline... 

Matyus et al. described a cascade Knovenagel/1,5-hydride transfer/cyclization reactions of 4-aryl-2-phenyl-1,4-benzoxazepine derivatives 19, which furnished fused 0,A -heterocycles 20 containing tetrahydro-l,4-benzoxazepine and tetrahydroquinoline moieties with high yields and diastereoselectivity (Scheme 9) [92]. Basically, under thermal conditions, the benzylidene intermediate I generated in situ... 

The in situ-generated iminium could also be exploited as hydride acceptor, via which inert C(sp )-H bond could be functionalized to C-N bond efficiently. Seidel et al. reported a trifluoroacetic acid-catalyzed cascade [1,6]-hydride transfer/cy-clization of 77 to synthesize 7,8,9-trisubstituted dihydropurine derivatives 78 (Scheme 27) [73]. TFA plays two roles in this process (1) promotion of imine formation and (2) protonation of imine for acceleration of the hydride shift process. Meth-Cohn and Volochnyuk et al. reported similar reactions in 1967 [71] and 2007, respectively [72]. 

Scheme 28 Synthesis of cyclic aminals via cascade 1,5-hydride transfer/cyclization...

Ketoesters could be exploited to generate iminium intermediate employed as hydride acceptor. Gong et al. reported a chiral Brpnsted acid 85-catalyzed asymmetric cascade [1,5]-hydride transfer/cyclization of 2-pyrrolidinyl phenyl ketoesters 82 with anilines 83, which produced the enantio-enriched cyclic aminals 84 (Scheme 29) [113]. The iminium subunit in intermediate I served as hydride acceptor, which was generated in situ through the condensation of o-aminoben-zoketone 82 with aniline 83 in the presence of 85. 

Tu et al. reported a Macmillan s catalyst 172-catalyzed asymmetric a-alkylation of tetrahydrofuran 170 containing an a,p-unsaturated aldehyde, via which chiral spiroether 171 could be prepared (Scheme 64) [129]. The sequential [l,5]-hydride transfer/cyclization was facilitated via cascade iminium/enamine activation. The presence of strong acid was indispensable to ensure sufficient electrophilicity of the iminium intermediate. Theoretically, substrate 170 reacts with 172 to give iminium intermediate I. Owing to the steric interaction of the bulky ferf-butyl group, the E enamine II is formed preferentially upon [1,5]-HT, which exists in two possible conformers III and IV. Because of dipole repulsion between the cyclic-oxocarbe-nium and enamine moieties in conformer III, IV is the more favored conformer, which undergoes intramolecular C-C bond formation to afford the final product 171. 

The methylene (or methine) adjacent to sulfur atom can also work as hydride donor. With reactive electrophilic moieties as hydride acceptors, the cascade [1,5]-hydride transfer/cyclization can occur to give thio-heterocycles. Alajarin and Vidal et al. contributed much to this chemistry. 

Alajarin and Vidal et al. discovered that under thermal conditions (refluxed in toluene), the single thioether 196 carrying ketenimine moiety could be transformed into 4-ethylthio-3,4-dihydroquinoline 197 in good yield via cascade [l,5]-hydride transfer/67 -ERC (Scheme 75) [56]. 

In the total synthesis of o-Homosteroid, Tietze et al. reported a BF3-OEt2-catalyzed cascade [1,5]-hydride transfer/cyclization of 219, which produced an unusually bridged steroid alkaloid 220 in 85 % yield at room temperature (Scheme 84) [137-139]. Although benzylic methine and imine in 219 are comparatively inactive hydride donor and acceptor, with the assistance of electron-donating methoxy group... 

Akiyama et al. first reported an unprecedented cascade [l,5]-hydride transfer/cyclization with non-benzylic methine as hydride donor (Scheme 90) [74]. Treatment of benzylidene barbituric acid 237 with 3 mol% Sc(OTf)3 in refluxing CICH2CH2CI for 24 h could furnish the desired tetraline 238 in excellent yield. Notably, the substrate with a linear side chain 239 did not give the desired product 240, even with a catalyst loading of 30 mol%. This result suggested that the substitution degree at the hydride-releasing carbon atom was crucial for the success of the cascade process. 

The synthesis is initiated by the organocatalyzed cascade that activates a,p-unsaturated aldehyde 8 with the formation of an iminium ion (Scheme 14.2). In this way, the imidazolidinone catalyst allows hydride transfer from the Hantzsch dihydropyridine 9 onto the highly activated conjugated alkene 11, which creates the nucleophilic enamine intermediate 12. Because of the chirality of the organocatalyst, stereoselective Michael addition (97% ee) to the adjacent enone occurs, with minor preference for the cis diastereomer (2 1 dr). Fortunately, this undesired diastereomer slowly epimerizes to the required trans isomer, which produces (-l-)-ricciocarpin A when treated with samarium triisopropoxide. Besides the Cannizzaro-like redox disproportionation, which allows the lactone producing Evans-Tihchenko reaction to occur, samarium(III) also enhances the epimerization to the trans isomer and therefore produces the desired isomer in high selectivity. 

Scheme 14.2 Imidazolinone-catalyzed hydride transfer/Michael addition cascade for the synthesis of (+)-ricciocarpin A.

These findings were extended to a set of very useful cascade reactions by the MacMiUan group [111]. In a first series 1,4-hydride additions were combined with aminations, oxidations, or Mannich reactions (Scheme 4.30). The hydride transfer was catalyzed by imidazoHdinone 9, whereas subsequent functionalization was realized by enamine catalysis through the deployment of proline. Depending on the chirality of proline used, optically pure anti- or syu-configured products 84-86 were isolated. 

After great success in the reduction of imines, quinolines, and pyridines. Rueping et al. designed a chiral phosphoric acid-catalyzed cascade reaction, in which enamines and enones are heated with Hantzsch ester la and (R)-6, then a Michael addition, cyclization, isomerization and hydride transfer reaction take place successively to afford chiral tetrahydropyridine 59 and azadecaUnone 60 products in excellent enantioselectiYities (Scheme 32.11) [33]. Remarkably,... 

The rapid development of organocatalysis impels chemists to discover new synthetic methodologies. Many important transformations that could only be realized by transition metal catalysis can now be achieved via organocatalysis. In 2010, Kim and coworkers reported a novel C-H bond functionalization reaction via a tandem 1,5-hydride transfer/ring closure sequence. Based on the iminium-enamine cascade activation of catalyst 33, the fused tetrahydroquino-Unes 35 could be synthesized from substrates 34 with good stereoselectivity. This is the first example of an organocatalytic intramolecular redox reaction (Scheme 36.10) [16]. 

The synthetic utility of this cascade reaction was underscored by the facile transformation of crotyl tiglate into 1,3-diol 137 (Scheme 7.39).82 Silver-catalyzed silylene transfer to crotyl tiglate produced silalactone 136 nearly quantitatively as a 97 3 mixture of diastereomers. Diol 137 was generated from silalactone after reduction of the lactone moiety with lithium aluminum hydride followed by oxidation of the C-Si bond 65>66 81... 

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