Ir-Catalyzed Synthesis

Miyaura has reported the iridium-catalyzed isomerization of unsymmetrical dia-Uyl ethers to ( )-allyl vinyl ethers [20]. The iridium catalyst 12 active for the isomerization of diallyl ethers was prepared in situ by bubbhng hydrogen into a red solution of [Ir(cod)(PPh2Me)2]PF(5 by the method reported by FeUdn (Eq. 3.1.11) 

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Figure 2 Suggested Scheme for the Ir-catalyzed synthesis of ethylbenzene.

Scheme 42 Ir-catalyzed synthesis of julolidine by transfer hydrogenation...

Madsen and coworkers reported Ir-catalyzed synthesis of 2,3,-disubstituted indoles from anilines and diols. A typical reaction involved the treatment of aniline with 2,3-butanediol in the presence of a catalytic amount of [Cp IrCl2]2 (lmol%) combined with methanesulfonic acid (5mol%) at 170 °C and gave 2,3-dimethylindole in 76% yield [160]. The reaction is proposed to proceed by the... 

Ir-Catalyzed Synthesis of Indole from 2-Aminoaryl Ethyl Alcohol... 

Grigg and coworkers reported that the Ir-catalyzed synthesis of indoles from 2-aminoaryl ethyl alcohols [20]. In a typical example, 2-aminophenyl ethyl alcohol and a catalytic amount of [Cp IrCl2]2 (2.5mol%) were combined with KOH (2 e quiv.) at 110 ° C for 24 h to give 3-benzylindole in 78% yield with high selectivity (Scheme 11.13). 

More examples for the cascade process involving transfer hydrogenation include the Ir-catalyzed synthesis of quinazolinones from primary alcohols and aminobenza-mides (Scheme 5.31) [31], and the Ir-catalyzed three-component reaction of secondary amines, aldehydes, and alkynes (Scheme 5.32) [32],... 

SCHEME 5.31 Ir-catalyzed synthesis of quinazolinones from primary alcohols and... 

Scheme 5.43 Ir-catalyzed synthesis and reactions of tert-butyidifluorosilylated arenes.

The Ir-catalyzed borylation of the indole nucleus is another important development that promises to find widespread use in complex molecule synthesis. Early reports include the functionalization of C(7) and also of C(2), reported by Malezcka and Smith and by Hartwig, respectively [39, 40]. In a report in 2011, Movassaghi, Miller, and coworkers demonstrated the borylation of tryptamine derivative 61 to afford 62 in 70 % yield [41]. This material was subjected to Suzuki-Miyaura cross coupling with 7-bromoindole (63) to set the stage for studying the oxidative rearrangement of 64, which would eventually provide diketopiperazine indole alkaloids such as asperazine (Scheme 11.11). 

N-Boc-N-(but-2-enoyl)amine is an excellent pronucleophile for the Ir-catalyzed allylic amination under salt-free conditions (cf. Table 9.3, entries 15-18). The products were subjected to RCM with good results, even upon application of the Grubbs I catalyst (Scheme 9.29) [27bj. The resultant N-Boc protected a,P-unsaturated y-lactams are valuable chiral intermediates with appUcations in natural products synthesis and medicinal chemistry. 

A synthesis of the prostaglandin analogue TEI-9826 is presented in Scheme 9.40 as an example of the use of an Ir-catalyzed aUyUc alkylation [44]. The allylic alkylation with a malonic amide of the Weinreb type as pronucleophile gave the substi-... 

Scheme 9.40 Synthesis of the prostaglandin analogue TEI-9826 via Ir-catalyzed allylic alkylation.

Ir-catalyzed alkylation with a nitro compound was applied in a synthesis of flS,2R)-tra s-2-phenylcyclopentanamine, a compound with antidepressant activity (Scheme 9.41) [45]. The reaction of cinnamyl methyl carbonate with 4-nitro-l-butene gave the substitution product with 93% ee in 82% yield. A Grubbs I catalyst sufficed for the subsequent RCM. Further epimerization with NEts yielded a trans-cyclopentene in 83% yield via the two steps, while additional reduction steps proceeded in 90% yield. 

A combination of allylic amination and RCM was used for the synthesis of fSj-nicotine (Scheme 9.42) [76]. The Ir-catalyzed amination of methyl 3-(3-pyridyl)-allyl... 

Cycloisomerization represents another approach for the construction of cyclic compounds from acyclic substrates, with iridium complexes functioning as efficient catalysts. The reaction of enynes has been widely studied for example, Chatani et al. reported the transformation of 1,6-enynes into 1-vinylcyclopentenes using [lrCl(CO)3]n (Scheme 11.26) [39]. In contrast, when 1,6-enynes were submitted in the presence of [lrCl(cod)]2 and AcOH, cyclopentanes with two exo-olefin moieties were obtained (Scheme 11.27) [39]. Interestingly, however, when the Ir-DPPF complex was used, the geometry of olefinic moiety in the product was opposite (Scheme 11.28) [17]. The Ir-catalyzed cycloisomerization was efficiently utilized in a tandem reaction along with a Cu(l)-catalyzed three-component coupling, Diels-Alder reaction, and dehydrogenation for the synthesis of polycyclic pyrroles [40]. 

A thorough investigation of the composition of reaction mixtures has revealed (86MI2) that the KOH/DMSO-catalyzed synthesis of pyrroles from ketoximes and acetylene is accompanied by the formation of Z-l-(2-methylthiovinyl)pyrroles (99), which can be isolated in a yield of about 0.1% (Scheme 48). The pyrroles 99a-c are characterized in detail (86MI3) by H-NMR (Table XXV). I3C-NMR, IR and mass spectra. 

The Ir-catalyzed enantioselective allylic substitution reaction can be used for the synthesis of -substituted a-amino acids . For example, the enantioselective Ir-catalyzed allylic substitution of 3-arylallyl diethyl phosphates 5.24 with pronucleophile diphenylimino gly-cinate 5.25 is achieved up to 98% ee by using bidentate chiral phosphite ligand 5.26. By changing the base, both diastereoisomeric substitution products 5.27a and 5.27b could be formed selectively. 

In Section 9-4-3, we mentioned that cationic Ir catalysts (sometimes called Crabtree catalysts) are quite active for hydrogenation of highly substituted C=C bonds. Moreover, asymmetric Ir-catalyzed hydrogenation of an imine is a key step in the industrial-scale synthesis of the herbicide (S)-metolachlor (Section 9-7-2). In addition to these applications, relatively recent work has shown that cationic Ir(I) complexes bonded to chiral ligands can catalyze asymmetric hydrogenation of unfunctionalized C=C bonds (i.e., C=C bonds to which no polar functional groups, such as C=0, are attached). 

More recently, a protocol was elucidated by Malezcka and Smith to produce aryl borate esters directly without first producing aryl halides.144 The reaction involves an Ir-catalyzed C-H activation (Section 7-2-1) to yield the aryl borate, which can then be used directly in Suzuki cross-coupling (equation 12.71). This new development adds another green aspect to Suzuki cross-coupling, which is already a relatively green synthesis tool. 

Murphy JM, Tzschucke CC, Hartwig JF (2007) One-pot synthesis of arylboronic acids and aryl trifluoroborates by Ir-catalyzed borylation of arenes. Org Lett 9 757... 

A remarkable increase in catalyst efficiency in SCCO2 as compared to conventional solvents was observed for the Ir-catalyzed enantioselective hydrogenation of imines shown in Scheme 12.12 [34]. Imine hydrogenation is a key step in the commercial synthesis of (S)-metolachlor, a commercial herbicide produced by Novartis in Switzerland. The reaction is approximately zero-order with respect to substrate in CO2 whereas it slows down dramatically at higher conversion in the organic solvent (Fig. 12.8). Thus, the time required for quantitative conversion is reduced by a factor of 20 when changing from the conventional to the supercritical solvent ... 

SCH EME 2 Synthesis of (H-)-prosopmine (5) and (+)-prosophylline (6) using Ir-catalyzed allylic cyclization. 

On the basis of the above mechanistic studies, the You group designed an Ir-catalyzed tandem dearomatization/migration protocol for asymmetric synthesis of enantioenriched tetrahydro-p-carboline derivatives 190 (Table 6.16). The migratory group in this reaction is methylene adjacent... 

Scheme 6.84 Asymmetric synthesis of six-membered aza-spiroindolenines by Ir-catalyzed intramolecular allylic dearomatization of indoles reported by You.

Scheme 15.28 Benzo(dipyrrole) synthesis by Ir-catalyzed hydroamination.

Piericidin-related natural products were prepared and their absolute configurations established. The synthesis involved an Ir-catalyzed C-H activation to provide the hydroxypyridine, a Mukaiyama aldol reaction, and a Negishi coupling (13OL670). 

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