Carbon–hydrogen (C–H) and carbon–carbon (C–C) bonds are the main constituents of organic matter. Recent advances in C–H functionalization technology have vastly expanded our toolbox for organic synthesis1. By contrast, C–C activation methods that enable editing of the molecular skeleton remain limited2,3,4,5,6,7. Several methods have been proposed for catalytic C–C activation, particularly with ketone substrates, that are typically promoted by using either ring-strain release as a thermodynamic driving force4,6 or directing groups5,7 to control the reaction outcome. Although effective, these strategies require substrates that contain highly strained ketones or a preinstalled directing group, or are limited to more specialist substrate classes5. Here we report a general C–C activation mode driven by aromatization of a pre-aromatic intermediate formed in situ. This reaction is suitable for various ketone substrates, is catalysed by an iridium/phosphine combination and is promoted by a hydrazine reagent and 1,3-dienes. Specifically, the acyl group is removed from the ketone and transformed to a pyrazole, and the resulting alkyl fragment undergoes various transformations. These include the deacetylation of methyl ketones, carbenoid-free formal homologation of aliphatic linear ketones and deconstructive pyrazole synthesis from cyclic ketones. Given that ketones are prevalent in feedstock chemicals, natural products and pharmaceuticals, these transformations could offer strategic bond disconnections in the synthesis of complex bioactive molecules.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
The data supporting the findings of this study are available within the article and its Supplementary Information. Additional data are available from the corresponding authors upon request. Metrical parameters for the structure of 123 are available free of charge from the Cambridge Crystallographic Data Centre (https://www.ccdc.cam.ac.uk/) under reference number CCDC 1876535.
Karimov, R. R. & Hartwig, J. F. Transition-metal-catalyzed selective functionalization of C(sp 3)-H bonds in natural products. Angew. Chem. Int. Ed. 57, 4234–4241 (2018).
Murakami, M. & Ito, Y. Cleavage of carbon–carbon single bonds by transition metals. Top. Organomet. Chem. 3, 97–129 (1999).
Chen, F., Wang, T. & Jiao, N. Recent advances in transition-metal-catalyzed functionalization of unstrained carbon–carbon bonds. Chem. Rev. 114, 8613–8661 (2014).
Souillart, L. & Cramer, N. Catalytic C–C bond activations via oxidative addition to transition metals. Chem. Rev. 115, 9410–9464 (2015).
Kim, D.-S., Park, W.-J. & Jun, C.-H. Metal–organic cooperative catalysis in C–H and C–C bond activation. Chem. Rev. 117, 8977–9015 (2017).
Fumagalli, G., Stanton, S. & Bower, J. F. Recent methodologies that exploit C–C single-bond cleavage of strained ring systems by transition metal complexes. Chem. Rev. 117, 9404–9432 (2017).
Dreis, A. & Douglas, C. in C–C Bond Activation (ed. Dong, G.) 85–110 (Springer, Berlin, 2014).
Schleyer, P. V. R. & Pühlhofer, F. Recommendations for the evaluation of aromatic stabilization energies. Org. Lett. 4, 2873–2876 (2002).
Santen, R. J., Brodie, H., Simpson, E. R., Siiteri, P. K. & Brodie, A. History of aromatase: saga of an important biological mediator and therapeutic target. Endocr. Rev. 30, 343–375 (2009).
King, R. B. & Efraty, A. Pentamethylcyclopentadienyl derivatives of transition metals. II. Synthesis of pentamethylcyclopentadienyl metal carbonyls from 5-acetyl-1,2,3,4,5-pentamethylcyclopentadiene. J. Am. Chem. Soc. 94, 3773–3779 (1972).
Crabtree, R. H., Dion, R. P., Gibboni, D. J., Mcgrath, D. V. & Holt, E. M. Carbon–carbon bond cleavage in hydrocarbons by iridium complexes. J. Am. Chem. Soc. 108, 7222–7227 (1986).
Halcrow, M. A., Urbanos, F. & Chaudret, B. Aromatization of the B-ring of 5,7-dienyl steroids by the electrophilic ruthenium fragment “[Cp*Ru]+”. Organometallics 12, 955–957 (1993).
Youn, S. W., Kim, B. S. & Jagdale, A. R. Pd-catalyzed sequential C–C bond formation and cleavage: evidence for an unexpected generation of arylpalladium(ii) species. J. Am. Chem. Soc. 134, 11308–11311 (2012).
Smits, G., Audic, B., Wodrich, M. D., Corminboeuf, C. & Cramer, N. A β-Carbon elimination strategy for convenient in situ access to cyclopentadienyl metal complexes. Chem. Sci. 8, 7174–7179 (2017).
Padwa, A. & Pearson, W. H. Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry toward Heterocycles and Natural Products (John Wiley & Sons, New York, 2003).
Le Fevre, G. & Hamelin, J. Existence d’une forme N–H stable de pyrazoline-4 lors de l’aromatisation de pyrazolidines 3,3-disubstituées en pyrazole. Mécanisme de la réaction. Tetrahedron Lett. 19, 4503–4506 (1978).
Tian, M., Shi, X., Zhang, X. & Fan, X. Synthesis of 4-acylpyrazoles from saturated ketones and hydrazones featured with multiple C(sp 3)–H bond functionalization and C–C bond cleavage and reorganization. J. Org. Chem. 82, 7363–7372 (2017).
Xu, Y., Young, M. C. & Dong, G. Catalytic coupling between unactivated aliphatic C–H bonds and alkynes via a metal–hydride pathway. J. Am. Chem. Soc. 139, 5716–5719 (2017).
Pan, S. & Shibata, T. Recent advances in iridium-catalyzed alkylation of C–H and N–H bonds. ACS Catal. 3, 704–712 (2013).
Xia, Y., Lu, G., Liu, P. & Dong, G. Catalytic activation of carbon–carbon bonds in cyclopentanones. Nature 539, 546–550 (2016).
Tsuji, J. & Ohno, K. Organic syntheses by means of noble metal compounds XXI. Decarbonylation of aldehydes using rhodium complex. Tetrahedron Lett. 6, 3969–3971 (1965).
Murphy, S. K., Park, J.-W., Cruz, F. A. & Dong, V. M. Rh-catalyzed C–C bond cleavage by transfer hydroformylation. Science 347, 56–60 (2015).
Zultanski, S. L. & Fu, G. C. Nickel-catalyzed carbon–carbon bond-forming reactions of unactivated tertiary alkyl halides: Suzuki arylations. J. Am. Chem. Soc. 135, 624–627 (2013).
Mei, T.-S., Patel, H. H. & Sigman, M. S. Enantioselective construction of remote quaternary stereocentres. Nature 508, 340–344 (2014).
Fessard, T. E. C., Andrews, S. P., Motoyoshi, H. & Carreira, E. M. Enantioselective preparation of 1,1-diarylethanes: aldehydes as removable steering groups for asymmetric synthesis. Angew. Chem. Int. Ed. 46, 9331–9334 (2007).
Chu, L., Ohta, C., Zuo, Z. & Macmillan, D. W. C. Carboxylic acids as a traceless activation group for conjugate additions: a three-step synthesis of (±)-pregabalin. J. Am. Chem. Soc. 136, 10886–10889 (2014).
Qin, T. et al. Nickel-catalyzed Barton decarboxylation and Giese reactions: a practical take on classic transforms. Angew. Chem. Int. Ed. 56, 260–265 (2017).
Candeias, N. R., Paterna, R. & Gois, P. M. P. Homologation reaction of ketones with diazo compounds. Chem. Rev. 116, 2937–2981 (2016).
Karrouchi, K. et al. Synthesis and pharmacological activities of pyrazole derivatives: a review. Molecules 23, 134 (2018).
Hong, X. et al. Mechanism and selectivity of N-triflylphosphoramide catalyzed (3+ + 2) cycloaddition between hydrazones and alkenes. J. Am. Chem. Soc. 136, 13769–13780 (2014).
This project was supported by NIGMS (R01GM109054). Y.X. acknowledges financial support from a Charles H. Viol Fellowship and a William Rainey Harper Dissertation Fellowship from the University of Chicago and a Bristol-Myers Squibb Graduate Fellowship. P.Z. acknowledges a Joint PhD Student Scholarship 2016 from China Scholarship Council (file number 201603170182). P.L. thanks the NSF (CHE-1654122) for funding. Calculations were performed at the Center for Research Computing at the University of Pittsburgh. L. Deng is acknowledged for the donation of substrate 140. J. Zhu is acknowledged for conducting several control experiments.
Nature thanks Vy Maria Dong and the other anonymous reviewer(s) for their contribution to the peer review of this work.
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Extended data figures and tables
Ac, acetyl. MS, molecular sieves. aAll yields are isolated yields. bThe yield refers to the key C–C activation reaction using pre-formed hydrazone as the substrate. For detailed experimental procedures, see Supplementary Information.
aAll yields are isolated yields. bThe yield refers to the key C–C activation reaction using pre-formed hydrazone as the substrate. c15 mol% Ir catalyst and 15 mol% L1 were used. For detailed experimental procedures, see Supplementary Information.
a, Free-energy profiles of the aromatization-driven C–C bond activation of dihydropyrazole 165. Calculations were performed at the M06-L/6-311+G(d,p)‒SDD/SMD(1,4-dioxane)//B3LYP/6-31G(d)‒SDD level of theory. The less favourable β-C elimination pathways with and without pyridine coordination (168-TS and 167-TS, respectively) are shown in blue. The NICS(1)zz aromaticity index was calculated at the B3LYP/6-311+G(d,p)‒SDD level of theory to describe the aromaticity of the pyrazole ring (highlighted in green) in 159, 160-TS and 161. The variation of NICS(1)zz indicates a substantial increase in aromaticity during the homolytic C–C bond cleavage. ΔG, change in Gibbs free energy; ΔH, change in enthalpy. b, Comparison between homolytic C–C bond cleavage of dihydropyrazole 165 and pyrazolidine 165ʹ (165ʹ without the driving force of aromatization). See Supplementary Information section 3.2.2 for details.
About this article
Silver-Catalyzed Site-Selective Ring-Opening and C–C Bond Functionalization of Cyclic Amines: Access to Distal Aminoalkyl-Substituted Quinones
Organic Letters (2019)
Nachrichten aus der Chemie (2019)