Waseda University
Doctor Thesis Synopsis
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Thesis Theme
Cationic Iridium-Catalyzed Synthesis Initiated by the Cleavage of Inactive Bonds
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Shiguang PAN
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(Major in Chemistry and Biochemistry, Research on Reaction Organic Chemistry)
April, 2013
No.
1
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 unactivated C-H and N-H 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. Iridium complexes have also been shown to be efficient catalysts for the direct functionalization of C-H and N-H bonds. In this thesis, the author reveals that cationic iridium complexes showed high catalytic activity in the direct formation of C-C and N-C bonds initiated by the oxidative 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 are 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 studies 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 were 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 quinoline was the best directing group and the enantiomeric
excess reached 98%. Methyl-substituted 2-(ethylamino)pyridines were also tested in this transformation.
Dependent on the position of the methyl group on the pyridine ring, the yield and ee were changed: compared with pyridine itself as directing group, the yields and enantiomeric excesses generally decreased. The coordination of the nitrogen in the pyridine ring to Ir would be crucial for the reaction efficiency and enantiomeric excess. The removal of pyridine group gave the chiral amine without a loss of enantiomeric excess, and the absolute configuration was determined to be S form. Mechanistic studies revealed that pyridine-directed cleavage of secondary sp3 C-H bond adjacent to nitrogen atom was likely to be the initial step in the present transformation, and two steps of C-H bond cleavage and hydroiridation are reversible. This transformation represents the first example of a highly enantioselective C-H bond activation of a methylene group, not at allylic or benzylic position.
Chapter 3 describes a chiral cationic iridium complex-catalyzed an intermolecular regio- and enantioselective hydroamination of styrene derivatives with various heteroaromatic amines under the solvent-free condition. This reaction proceeded with 10 mol% 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 iridium catalyst, but a longer reaction was required. The regioselectivity was perfect, and an 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 pyrimidine, pyrazine, and quinoline, were tolerated in this transformation. The reaction of 6-methyl-2-aminopyridine with styrene gave the products in high combined yield of anti-Markovnikov and Markovnikov adducts, and the former was minor. This result indicated that the coordination of nitrogen of the pyridine to Ir would be crucial for the control of the regioselectivity. Mechanistic studies revealed that pyridine-directed cleavage of N-H bond of 2-aminopyridine was likely to be the initial step in the present 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-alkylpyridone, 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 NaOAc (1.1 equiv). Significant electronic and steric effects on the reactivities 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 NaOAc. The β-hydrogen elimination was completely suppressed by adding NaOAc. For 2-alkoxypyridines bearing a primary O-alkyl group, the O- to N-alkyl migration proceeded efficiently without NaOAc or solvent, and the reaction gave the corresponding N-alkylpyridones in good to excellent yields at lower
No.
3
catalyst loadings. The protocol is a facile way of synthesizing N-alkyl pyridones bearing a primary alkyl group.
Mechanistic studies revealed that there were two possible pathways for C-O bond cleavage: a) direct sp3 C-O bond activation, and b) sp3 C-H bond activation/isomerization, which followed by O- to N-alkyl migration. Trace amounts of crossover products (<5%) were observed by gas chromatography-mass spectrometry analysis. These results indicated that this transformation did not generate free radicals or ionic intermediates.
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 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 authors 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 of directing group screening, 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, the reaction of N-acetylindole with styrene derivatives gave the linear 2-alkylindoles in high to excellent selectivity in the presence of 10 mol%
[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, vinyl ketone, and ethyl acrylate, the [Ir(cod)2]BF4-racemic-2,2'- bis(diphenylphosphino)-1,1'-binaphthyl (rac-BINAP) catalyst realized perfect linear selectivity. In the case of N-benzoylindole with styrene derivatives, a variety of branched 2-alkylindoles were obtained in high to perfect selectivity in the presence of 10 mol% [Ir(cod)2]BARF with (R)-(+)-7,7'-bis(diphenylphosphino)-2,2',3,3'-tetra- hydro-1,1'-spirobiindane ((R)-SDP). However, in the reaction of aliphatic 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 were 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 cationic iridium catalysts. Enantioselective variants of some reactions have also been reported. The author also gave the possible mechanisms for these transformations in this thesis.
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(List of research achievements for application of doctorate (Dr. of Science), Waseda University)
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“Ir(I)-Catalyzed Synthesis of N-Substituted Pyridones from 2-Alkoxypyridines via C-O Bond Cleavage”
Org. Lett. 2013, 15, 1902-1905.
Shiguang Pan, Naoto Ryu, Takanori Shibata
“Recent Advances in Iridium-Catalyzed Alkylation of C-H and N-H Bonds”
ACS Catal. 2013, 3, 704-712.
Shiguang Pan, Takanori Shibata
“Ir(I)-Catalyzed C-H Bond Alkylation of C2-Position of Indole with Alkenes: Selective Synthesis of Linear or Branched 2-Alkylindoles”
J. Am. Chem. Soc. 2012, 134, 17474-17477.
Shiguang Pan, Naoto Ryu, Takanori Shibata
“Cationic Iridium-Catalyzed Enantioselective Activation of Secondary sp3 C-H Bond Adjacent to Nitrogen Atom”
Tetrahedron 2012, 68, 9009-9015.
Shiguang Pan, Yusuke Matsuo, Kohei Endo, Takanori Shibata
“Ir(I)-catalyzed Intermolecular Regio- and Enantioselective Hydroamination of Alkenes with Heteroaromatic Amines”
Org. Lett. 2012, 14, 780-783.
Shiguang Pan, Kohei Endo, Takanori Shibata
“Ir(I)-catalyzed Enantioselective Secondary sp3 C-H Bond Activation of 2-(Alkylamino)pyridines with Alkenes”
Org. Lett. 2011, 13, 4692-4695.
Shiguang Pan, Kohei Endo, Takanori Shibata
No.2
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(List of research achievements for application of doctorate (Dr. of Dr. of Science), Waseda University)
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“Ir(I)-Catalyzed Enantioselective Activation of Secondary sp3 C-H Bond Adjacent to Nitrogen Atom”
The 12th International Kyoto Conference on New Aspects of Organic Chemistry, Rihga Royal Hotel (Kyoto), Nov. 2012, PA-112.
Shiguang Pan, Yusuke Matsuo, Takanori Shibata
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“Ir(I)-Catalyzed Enantioselective Secondary sp3 C-H Bond Activation of 2-(Alkylamino)pyridines with Alkenes”
The 6th GCOE International Symposium on “Practical Chemical Wisdom”, Waseda University (Tokyo), Dec. 2011, P9.
Shiguang Pan, Kohei Endo, Takanori Shibata
