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Pyridine N-Oxide vs Pyridine Substrates for Rh(III)-Catalyzed Oxidative C-H Bond Functionalization.
J Am Chem Soc. 2015 Aug 12; 137(31):9843-54.JA

Abstract

The origin of the high reactivity and site selectivity of pyridine N-oxide substrates in O-pivaloyl hydroxamic acid-directed Rh(III)-catalyzed (4+2) annulation reactions with alkynes was investigated computationally. The reactions of the analogous pyridine derivatives were previously reported to be slower and to display poor site selectivity for functionalization of the C(2)-H vs the C(4)-H bonds of the pyridine ring. The N-oxide substrates are found to be more reactive overall because the directing group interacts more strongly with Rh. For N-oxide substrates, alkyne insertion is rate-limiting and selectivity-determining in the reaction with a dialkyl alkyne, but C-H activation can be selectivity-determining with other coupling partners such as terminal alkynes. The rates of reaction with a dialkyl alkyne at the two sites of a pyridine substrate are limited by two different steps: C-H activation is limiting for C(2)-functionalization, while alkyne insertion is limiting for C(4)-functionalization. Consistent with the observed poor site selectivity in the reaction of a pyridine substrate, the overall energy barriers for functionalization of the two positions are nearly identical. High C(2)-selectivity in the C-H activation step of the reaction of the N-oxide is due to a cooperative effect of the C-H Brønsted acidity, the strength of the forming C-Rh bond, and intramolecular electrostatic interactions between the [Rh]Cp* and the heteroaryl moieties. On the other hand, some of these forces are in opposition in the case of the pyridine substrate, and C(4)-H activation is moderately favored overall. The alkyne insertion step is favored at C(2) over C(4) for both substrates, and this preference is largely influenced by electrostatic interactions between the alkyne and the heteroarene. Experimental results that support these calculations, including kinetic isotope effect studies, H/D exchange studies, and results using a substituted pyridine, are also described.

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Publisher Full Text (DOI)

Authors+Show Affiliations

Neufeldt SR
†Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States.
Jiménez-Osés G
†Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States.
Huckins JR
‡Process Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Thiel OR
‡Process Development, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320, United States.
Houk KN
†Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095, United States.

MeSH

AlkynesBinding SitesCarbonCatalysisHydrogenKineticsModels, MolecularMolecular ConformationOxidation-ReductionPyridinesRhodium

Pub Type(s)

Comparative Study
Journal Article
Research Support, U.S. Gov't, Non-P.H.S.

Language

eng

PubMed ID

26197041

Citation

Neufeldt, Sharon R., et al. "Pyridine N-Oxide Vs Pyridine Substrates for Rh(III)-Catalyzed Oxidative C-H Bond Functionalization." Journal of the American Chemical Society, vol. 137, no. 31, 2015, pp. 9843-54.
Neufeldt SR, Jiménez-Osés G, Huckins JR, et al. Pyridine N-Oxide vs Pyridine Substrates for Rh(III)-Catalyzed Oxidative C-H Bond Functionalization. J Am Chem Soc. 2015;137(31):9843-54.
Neufeldt, S. R., Jiménez-Osés, G., Huckins, J. R., Thiel, O. R., & Houk, K. N. (2015). Pyridine N-Oxide vs Pyridine Substrates for Rh(III)-Catalyzed Oxidative C-H Bond Functionalization. Journal of the American Chemical Society, 137(31), 9843-54. https://doi.org/10.1021/jacs.5b03535
Neufeldt SR, et al. Pyridine N-Oxide Vs Pyridine Substrates for Rh(III)-Catalyzed Oxidative C-H Bond Functionalization. J Am Chem Soc. 2015 Aug 12;137(31):9843-54. PubMed PMID: 26197041.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pyridine N-Oxide vs Pyridine Substrates for Rh(III)-Catalyzed Oxidative C-H Bond Functionalization. AU - Neufeldt,Sharon R, AU - Jiménez-Osés,Gonzalo, AU - Huckins,John R, AU - Thiel,Oliver R, AU - Houk,K N, Y1 - 2015/08/03/ PY - 2015/7/22/entrez PY - 2015/7/22/pubmed PY - 2016/6/14/medline SP - 9843 EP - 54 JF - Journal of the American Chemical Society JO - J Am Chem Soc VL - 137 IS - 31 N2 - The origin of the high reactivity and site selectivity of pyridine N-oxide substrates in O-pivaloyl hydroxamic acid-directed Rh(III)-catalyzed (4+2) annulation reactions with alkynes was investigated computationally. The reactions of the analogous pyridine derivatives were previously reported to be slower and to display poor site selectivity for functionalization of the C(2)-H vs the C(4)-H bonds of the pyridine ring. The N-oxide substrates are found to be more reactive overall because the directing group interacts more strongly with Rh. For N-oxide substrates, alkyne insertion is rate-limiting and selectivity-determining in the reaction with a dialkyl alkyne, but C-H activation can be selectivity-determining with other coupling partners such as terminal alkynes. The rates of reaction with a dialkyl alkyne at the two sites of a pyridine substrate are limited by two different steps: C-H activation is limiting for C(2)-functionalization, while alkyne insertion is limiting for C(4)-functionalization. Consistent with the observed poor site selectivity in the reaction of a pyridine substrate, the overall energy barriers for functionalization of the two positions are nearly identical. High C(2)-selectivity in the C-H activation step of the reaction of the N-oxide is due to a cooperative effect of the C-H Brønsted acidity, the strength of the forming C-Rh bond, and intramolecular electrostatic interactions between the [Rh]Cp* and the heteroaryl moieties. On the other hand, some of these forces are in opposition in the case of the pyridine substrate, and C(4)-H activation is moderately favored overall. The alkyne insertion step is favored at C(2) over C(4) for both substrates, and this preference is largely influenced by electrostatic interactions between the alkyne and the heteroarene. Experimental results that support these calculations, including kinetic isotope effect studies, H/D exchange studies, and results using a substituted pyridine, are also described. SN - 1520-5126 UR - https://www.unboundmedicine.com/medline/citation/26197041/Pyridine_N_Oxide_vs_Pyridine_Substrates_for_Rh_III__Catalyzed_Oxidative_C_H_Bond_Functionalization_ DB - PRIME DP - Unbound Medicine ER -