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Cationic Iridium-Catalyzed Synthesis Initiated by the Cleavage of Inactive Bonds
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Shiguang PAN
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2013 . 7 9
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The direct functionalization of inactive bonds, such as C-H and N-H bonds, is an ideal transformation in organic synthesis, because C-H and N-H bonds are ubiquitous in organic molecules, and pre-activation of substrates is unnecessary. Thus, synthetic protocols that begin with inactive bond cleavage have attracted much attention from both academia and industry over the past decade. Generally, the C-H and N-H bonds are inert in mild reaction conditions. Therefore, transition metal catalysts have been applied for C-H and N-H bond functionalization. Direct C-C and N-C bond formations via inactive bond functionalization represent economically attractive alternatives to traditional cross-coupling reactions of haloarenes with organometallic reagents. To date, various transition metal catalysts (Pd, Rh, Ru, Cu, Fe, etc.) have been reported to catalyze the direct functionalization of C-H and N-H bonds. Despite these advances, many difficulties, such as the control of chemo-, regio- and enantioselectivity, remain unsolved. Therefore, the enantioselective functionalization of C-H and N-H bonds is highly demanded. On the other hand, iridium complexes were relatively newcomers in the area of C-H and N-H bond functionalization, but they have also been reported as efficient catalysts for the direct functionalization of C-H and N-H bonds. In this thesis, the author revealed that cationic iridium complexes showed high catalytic activity in the direct formation of C-C and N-C bonds initiated by the cleavage of C-H and N-H bonds. Enantioselective variants of some reactions have also been developed. The author also discussed the reaction mechanisms of the newly developed reactions in this thesis.
Chapter 1 describes the general introduction of this thesis. The backgrounds and the purpose of this thesis were discussed. Synthetic protocols that begin with inactive C-H and N-H bonds cleavage are important transformations in organic synthesis, especially regard to C-C bond formations through transition metal catalysis.
However, the enantioselective and catalytic C-C bond formation is still rare and is highly demanded. In this thesis, the author studied on the methodology of the enantioselective C-H and N-H bond activation by using chiral iridium catalysts.
Chapter 2 describes the chiral cationic iridium-catalyzed enantioselective activation of secondary sp3 C-H bond adjacent to nitrogen atom. There have been relatively few studies of catalytic sp3 C-H bond activation, due to the greater stability and lower reactivity of sp3 C-H bonds than sp2 C-H bonds. Moreover, the cleavage of secondary sp3 C-H bond is more difficult but more fascinating because the direct generation of a chiral center can be possible. In this work, a wide variety of 2-(alkylamino)pyridines and alkenes were selectively transformed into the corresponding chiral amines with moderate to almost perfect enantiomeric excesses in the presence of a catalytic amount (10 mol%) of bis(1,5-cyclooctadiene)iridium tetrafluoroborate ([Ir(cod)2]BF4) with (S)-(-)-2,2'-bis(di-p-tolylphosphino)-1,1'-binaphthyl ((S)-tolBINAP). In particular, the reaction of 2-(ethylamino)pyridine and ethyl acrylate gave the desired product with 99% enantiomeric excess. Alkynes were also investigated as coupling partners. The effect of alkyl structure on the nitrogen atom of amino group and directing groups was studied. In the case of a longer alkyl group, a higher reaction temperature and a longer reaction time were required for this transformation. In contrast, the reaction of 2-(alkylamino)pyridine possessing a bulky alkyl group did not proceed. The author also screened various nitrogen-containing heterocycles as directing groups and found that 1-quinolyl group was best, and the enantiomeric excess reached 98%. This transformation represents the first example of highly enantioselective C-H bond activation of
2 methylene group, not at allylic or benzylic position.
Chapter 3 describes a chiral cationic iridium complex-catalyzed intermolecular regio- and enantioselective hydroamination of styrene derivatives with various heteroaromatic amines under the solvent-free conditions.
This reaction proceeded with 10 mol% of bis(1,5-cyclooctadiene)iridiumtetrakis[3,5-bis(trifluoromethyl)phenyl]
-borate ([Ir(cod)2]BARF) with (S)-(+)-1,13-bis(diphenylphosphino)-7,8-dihydro-6H-dibenzo[f,h][1,5]dioxonin ((S)-C3-TUNEPHOS). The reaction could also be achieved with a low loading of the iridium catalyst, but a longer reaction time was required. The regioselectivity was perfect, and a branched amine was the single product even in the reaction of a bulky alkene. Norbornene derivatives were good substrates and high enantiomeric excesses were achieved. A range of heteroaromatic amines, such as 2-aminopyrimidine, 2-aminopyrazine, and 1-aminoisoquinoline, were tolerated in this transformation.
Chapter 4 describes the cationic iridium-catalyzed synthesis of N-substituted pyridones from 2-alkoxypyridines via C-O bond cleavage. The synthetic protocols that begin with 2-alkoxypyridines via O-to-N-alkyl migration have attracted significant attention for the efficient synthesis of N-alkylpyridones, because 2-alkoxypyridines can be easily synthesized by the nucleophilic aromatic substitution of 2-halopyridines.
In this work, the O-to-N-alkyl migration in 2-alkoxypyridines via C-O bond cleavage was achieved by using a cationic iridium catalyst. Various N-substituted pyridones were obtained in moderate to good yields. The reaction of 2-alkoxypyridine bearing a secondary O-alkyl group could be achieved to give the corresponding N-alkylpyridones in the presence of [Ir(cod)2]BARF (10 mol%) with sodium acetate (1.1 equiv). Significant electronic and steric effects on the reactivity of substrates were observed in this transformation. The reaction of 2-alkoxypyridine possessing an electron-withdrawing group required a longer reaction time. Low reactivity was observed in the reaction of 2-alkoxypyridine bearing a bulky O-alkyl group. A control experiment was conducted to clarify the role of sodium acetate and the β-hydrogen elimination was completely suppressed by adding sodium acetate. For 2-alkoxypyridines bearing a primary O-alkyl group, the O-to-N-alkyl migration proceeded efficiently without sodium acetate or solvent, and the reaction gave the corresponding N-alkylpyridones in good to excellent yields at lower catalyst loadings.
Chapter 5 describes the cationic iridium-catalyzed C-H bond alkylation of C2-position of indole with alkenes:
selective synthesis of linear or branched 2-alkylindole. 2-Alkylindoles serve as precursors for a variety of medicinally important alkaloids and their analogs. However, the examples of direct C2-alkylation via transition metal-catalyzed C−H bond activation are still limited, and only a Pd-catalyzed example has been recently reported, where a stoichiometric amount of norbornene was used. Therefore, the direct C2-alkylation of indole is in high demand. In this work, the author developed a cationic iridium-catalyzed synthesis of linear or branched 2-alkylindoles via C-H bond activation. The selectivity of linear or branched product was controlled by the directing group and ligand. The preliminary studies in this area focused on the identification of an appropriate directing group. As a result, the reaction of N-acetylindole with styrene gave the linear 2-alkylindole as a major product, while the reaction of N-benzoylindole with styrene gave the branched 2-alkylindole as a major product.
With further optimization of phosphine ligands of the iridium catalyst, the reaction of N-acetylindole with styrene derivatives gave the linear 2-alkylindoles in high to excellent selectivity in the presence of 10 mol%
3
[Ir(cod)2]BF4 with (S)-(-)-5,5'-bis[di(3,5-xylyl)phosphino]-4,4'-bi-1,3-benzodioxole ((S)-DM-SEGPHOS). In the reactions of acrylonitrile, methyl vinyl ketone, and ethyl acrylate, the [Ir(cod)2]BF4-racemic-2,2'- bis(diphenylphosphino)-1,1'-binaphthyl (rac-BINAP) catalyst realized almost perfect linear selectivity. In the case of N-benzoylindole with styrene derivatives, a variety of branched 2-alkylindoles were obtained in high to almost perfect selectivity in the presence of 10 mol% [Ir(cod)2]BARF with (R)-(+)-7,7'-bis(diphenylphosphino)- 2,2',3,3'-tetrahydro-1,1'-spirobiindane ((R)-SDP). In contrast, in the reaction of alkyl-substituted alkenes, the branched products were predominant regardless of the directing group and the ligand of the Ir catalyst. For example, the [Ir(cod)2]BF4-rac-BINAP-catalyzed reaction of N-acetylindole with 1-nonene gave the branched product predominantly. When a benzoyl group was used as a directing group, the branched product was obtained with excellent selectivity under the same reaction conditions. Mechanistic studies revealed that carbonyl-directed cleavage of C-H bond at C2-position of indole was likely to be the initial step in the present transformation, and two steps of C-H bond cleavage and alkene insertion would be reversible. The present protocol constitutes a new example of C2-alkylation of indoles.
Chapter 6 describes the summary of this thesis. In this thesis, the formation of C-C and N-C bonds was realized by the cleavage of C-H and N-H bonds using the cationic iridium catalysts. Enantioselective variants of some reactions have also been reported. The author also proposed the possible mechanisms for these transformations in this thesis.
The author revealed not only the high catalytic activity, but also the unique reactivity of cationic iridium catalysts: examples of actual accomplishments include enantioselective C-H bond activation, enantioselective and intermolecular hydroamination, synthesis of N-substituted pyridones via O-to-N-alkyl migration, and C2-selective alkylation of indoles. Therefore, his achievements have significant impact on this field and opened up doors for the development of efficient utilization of inactive bonds.
In summary, this is an outstanding thesis containing many scientific breakthroughs and Ph.D. degree is highly recommended.
2013.79
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