C-H bond activation has been extensively studied with (Cp*)M(L)n (M = Ir, Rh), but cobalt, the third member of this triad, has not previously been shown to activate sp3 C-H bonds. Further, practical functionalization of the metal alkyl products of oxidative addition has not been fully explored. Toward these ends, we have developed catalytic dehydrogenation of alkyl amines with a Co(I) catalyst. Amine substrates are protected with vinyl silanes, followed by catalytic transfer hydrogenation, to yield a broad range of stable protected enamines and 1,2-diheteroatom-substituted alkenes, including several unprecedented heterocycles. (Cp*)Co(VTMS)2 catalyzes transfer hydrogenation under surprisingly mild conditions with high chemo-, regio-, and diastereoselectivity, while tolerating additional functionality

Bolig, Andrew D.

Brookhart, Maurice

PubMed

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Activation of sp3 C-H Bonds with Cobalt(I): Catalytic Synthesis ofEnaminesAndrew D. Bolig and Maurice Brookhart*Department of Chemistry, University of North Carolina, Chapel Hill, North Carolina 27599-3290AbstractC-H bond activation has been extensively studied with (Cp*)M(L)n (M = Ir, Rh), but cobalt, the thirdmember of this triad, has not previously been shown to activate sp3C-H bonds. Further, practicalfunctionalization of the metal alkyl products of oxidative addition has not been fully explored.Towards these ends, we have developed catalytic dehydrogenation of alkyl amines with a Co(I)catalyst. Amine substrates are protected with vinyl silanes, followed by catalytic transferhydrogenation to yield a broad range of stable protected enamines and 1,2-diheteroatom substitutedalkenes, including several unprecedented heterocycles. (Cp*)Co(VTMS)2 catalyzes transferhydrogenation under surprisingly mild conditions with high chemo-, regio-, and diastereo-selectivity, while tolerating additional functionality.Twenty-five years after the seminal reports by Bergman1 and Jones2 on oxidative addition ofC-H bonds to (Cp*)M(L) complexes of iridium and rhodium respectively, extensive progresshas been made in mechanistic understanding,3 and functionalization for applications insynthesis4. Cobalt, the analogous metal from the first transition series, while known to activatesp2 aromatic and aldehydic C-H bonds5, has been notably absent from reports of sp3 C-Hactivation. In fact, experimental6 and computational7 studies have indicated that C-H bondsshould not oxidatively add to the 16-electron Co(I) center as they do to Ir and Rh. Thiscommunication describes for the first time the facile and highly selective activation andfunctionalization of sp3 C-H bonds by [(Cp*)Co(VTMS)2] (1) (VTMS = vinyltrimethyl silane),allowing synthesis of unique heterocycles.Direct functionalization of C-H bonds α to nitrogen is a particularly attractive transformation,but catalytic examples are still somewhat rare8. One strategy for functionalization of C-Hoxidative addition products is the net dehydrogenation of organic substrates,9 transforming C-H bonds into carbon-carbon bonds. In this area, our group has developed methodology for thesynthesis of silyl enol ethers10 and 1,2- diheteroatom alkenes11 via [(Cp*)Rh(VTMS)2] (2) -Email: mbrookhart@unc.edu.NIH Public AccessAuthor ManuscriptJ Am Chem Soc. Author manuscript; available in PMC 2008 November 28.Published in final edited form as:J Am Chem Soc. 2007 November 28; 129(47): 14544–14545. doi:10.1021/ja075694r.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptcatalyzed intramolecular transfer dehydrogenation. Enamines12 are versatile reactiveintermediates for organic synthesis, so we explored the application of this strategy to theirformation (Scheme 1).Goldman13 has reported synthesis of enamines from 3° alkyl amines via Ir-catalyzed inter-molecular hydrogen transfer. Our intra-molecular approach to hydrogen transfer iscomplementary and applicable to (protected) 2° amines. The silicon protecting group servesadditionally as hydrogen acceptor and directing group. This strategy affords protectedendocyclic enamines which are difficult to access via conventional methodology.Substrate and catalyst screening was efficiently conducted in screw-cap NMR tubes withC6D12 for convenient monitoring of reaction progress. Preparative scale reactions were thenperformed in Kontes flasks in pentane solvent (5 mmol substrate, 2% Co catalyst loading, 6h,80°C) with isolated yields of metal-free products up to 90% (See Supporting Information fordetails).Initially we explored conversion of piperidine 3 into protected tetrahydropyridine 4, anattractive target both as a mimic of biological hydrogen transfer agents and as a syntheticintermediate.14 Unprotected endocyclic “enamines” of 2° amines generally react as, and areisolated as, the imine tautomer15, so (protected) enamines should be valuable synthons.Gratifyingly, rhodium catalyst 2 produced the desired enamine 4, albeit requiring 6 hours at140°C for conversion (Table 1, entry 1). In contrast, cobalt catalyst 1 afforded 4 in < 1h at 80°C (Table 1, entry 2). Encouraged by this rapid conversion under mild conditions, weinvestigated the scope of this Co-catalyzed transfer dehydrogenation.Subjection of 2- and 3-substituted piperidines (Entries 3 and 4) to cobalt-mediated transfercatalysis led to di-substituted olefins 6 and 8 respectively, as the only observable products withno isomerization to the thermodynamically more stable tri-substituted olefins even at longreaction times. Endocyclic enamines have been employed in natural products synthesis16, buttypically as the more substituted isomers available by previous methodology17.One hallmark of late-metal catalysts is their compatability with Lewis basic functionality.Nitrogen- and oxygen-containing functional groups are well tolerated by 1, allowing synthesisof dehydrogenated piperazine and morpholine derivatives (Entries 5 and 6, respectively).Sulfur apparently poisons the active cobalt species; only 13% conversion of 13 was observedwith 1, corresponding to a TON of <4. Rhodium catalyst 2 proved effective for this substrate,yielding clean transfer product 14.Unsaturated azacycles with ring size greater than 6 are rare18, yet 15 and 17 were transformedinto 7- and 8-membered N-protected enamines by this methodology. In the former case (entry9), starting material was consumed surprisingly rapidly (ca. 10 min), but additional specieswere observed at early reaction times which slowly isomerized to enamine 16. Intriguingly,these products vary in the position of the double bond (allylic- and homoallylic- amines),indicating oxidative addition of truly “unactivated” C-H bonds to the metal center (SeeSupporting Information for details).Next, we further probed the regioselectivity of this transformation with catalyst 1. Substrate19 contains two sites potentially amenable to dehydrogenation: the methylene groups of thediamine or those of the morpholine ring. After 30 minutes at 80°C, only 20 was observed, withno isomerization over several hours. This result establishes that this process is: 1) Applicableto linear as well as cyclic amines. (Primary enamines are notoriously difficult to prepare19, soprotected variants are expected to have synthetic utility.) 2) Regioselective; final productsobserved are consistent with activation of the C-H bond to the protected nitrogen. 3)Diastereoselective. Whereas the Z geometry is thermodynamically favored for 1,2-Bolig and Brookhart Page 2J Am Chem Soc. Author manuscript; available in PMC 2008 November 28.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscriptdiheteroatom-substituted olefins, only the E isomer was observed. 4) Consistent with intra-,not inter-molecular hydrogen transfer, as the morpholine moiety was not dehydrogenated.Cobalt catalyst 1 was ineffective for transfer hydrogenation of the substrate analogous to 19containing a free N-H (lacking the EDMS protecting group), indicating distinctchemoselectivity compared to Ir catalysts which produce imines from secondary amines20.These observations are consistent with a mechanism analogous to that for dehydrogenation ofprotected alcohols with 121. As such, it involves formation of the 16 e− intermediate [(Cp*)Co(mono-olefin)] and oxidative addition of an sp3 C-H bond (generally α to the heteroatom)to the cobalt(I) center. Migratory insertion of the vinyl silane into the cobalt hydride followedby β-hydride elimination (from the 3-position of the amine) and reductive elimination yieldsthe observed enamine products. The more rapid turnover of the Co system relative to the Rhsystem must stem in part from the lower barrier to dissociation of a vinyl group from the (Cp*)Co(bis-olefin) resting state22.In conclusion, we have demonstrated a convenient synthetic route to enamines based on cobalt-catalyzed hydrogen transfer of protected amines. This conversion is consistent with cobalt(I)sp3 C-H bond activation, reactivity which was previously held to be the exclusive domain ofthe heavier group 9 metals. Catalyst 1 exhibits not only high reactivity under milder conditionsthan the other members of its triad, but also impressive chemo-, regio-, diastereo-, and intra-molecular hydrogen transfer selectivity. Further investigations into the scope of thistransformation, mechanistic studies, and applications to synthesis are currently underway inthis laboratory.Supplementary MaterialRefer to Web version on PubMed Central for supplementary material.AcknowledgementsWe gratefully acknowledge funding by the National Institutes of Health (Grant No. GM 28939).References1. Janowicz AH, Bergman RG. J Am Chem Soc 1982;104:352.2. Jones WD, Feher FJ. J Am Chem Soc 1982;104:4240.3. Arndtsen BA, Bergman RG, Mobley TA, Peterson TH. Acc Chem Res 1995;28:154. (b) Jones WD,Feher FJ. Acc Chem Res 1989;22:91. (c) Halpern J. Inorg Chim Acta 1985;100:41.4. Wilson RM, Thalji RK, Bergman RG, Ellman JA. Org Lett 2006;8:1745. [PubMed: 16597156]andreferences therein (b) Godula K, Sames D. Science 2006;312:67. [PubMed: 16601184] (c) Cho J-Y,Tse MK, Holmes D, Maleczka RE Jr, Smith MR III. Science 2002;295:305. [PubMed: 11719693] (d)Chen H, Schlecht S, Semple TC, Hartwig JF. Science 2000;287:1995. [PubMed: 10720320]5. Lenges CP, Brookhart M, Grant BE. J Organometallic Chem 1997;528:199. (b) Lenges CP, BrookhartM. J Am Chem Soc 1997;119:3165. (c) Lenges CP, White PS, Brookhart M. J Am Chem Soc1998;120:6965. (d) Wadepohl H, Borchert T, Pritzkow H. J Chem Soc, Chem Comm 1995:1447.6. Bengali AA, Bergman RG, Moore CB. J Am Chem Soc 1995;117:3879.7. Siegbahn PEM. J Am Chem Soc 1996;118:1487. (b) Poli R, Smith KM. Eur J Inorg Chem 1999:877.8. Campos KR. Chem Soc Rev 2007;36:1069. [PubMed: 17576475]and references therein9. Burk MJ, Crabtree RH. J Am Chem Soc 1987;109:8025. (b) Liu F, Pak EB, Singh B, Jensen CM,Goldman AS. J Am Chem Soc 1999;121:4086.10. Lenges CP, White PS, Brookhart M. J Am Chem Soc 1999;121:4835.Bolig and Brookhart Page 3J Am Chem Soc. Author manuscript; available in PMC 2008 November 28.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author Manuscript11. Diaz-Requejo, MMar; DiSalvo, D.; Brookhart, M. J Am Chem Soc 2003;125:2038. [PubMed:12590518]12. RappoportZThe Chemistry of Enamines (Parts 1 & 2)WileyNew York1994 For a review of metal-mediated syntheses, see: (b) Dehli JR, Legros J, Bolm C. Chem Comm 2005:973. [PubMed:15719090]13. Zhang X, Fried A, Knapp S, Goldman AS. Chem Comm 2003:2060. [PubMed: 12934911]14. Beeken P, Fowler FW. J Org Chem 1980;45:1336. (b) Wenkert E, Dave KG, Haglid F, Lewis RG,Oishi T, Stevens RV, Terashima M. J Org Chem 1968;33:747. [PubMed: 5636614] (c) Cook NC,Lyons JE. J Am Chem Soc 1966;88:3396.15. Cook, AG., editor. Enamines: Synthesis, Structure, and Reactions. 2. Marcel Dekker; New York:1988. p. 46016. Evans DA, Bryan CA, Sims CL. J Am Chem Soc 1972;94:2891. (b) Evans DA. J Am Chem Soc1970;92:7593. (c) Wenkert E. Acc Chem Res 1968;1:78. (d) Dake GR, Fenster MDB, Hurley PB,Patrick BO. J Org Chem 2004;69:5668. [PubMed: 15307738]17. Takemiya A, Hartwig JF. J Am Chem Soc 2006;128:6042. [PubMed: 16669666]For exceptions, see:(b) Larivée A, Charette AB. Org Lett 2006;8:3955. [PubMed: 16928047] (c) Hegedus LS, McKearinJM. J Am Chem Soc 1982;104:2444.18. Cook, AG., editor. Enamines: Synthesis, Structure, and Reactions. 2. Marcel Dekker; New York:1988. p. 44219. Novak BM, Cafmeyer JT. J Am Chem Soc 2001;123:11083. [PubMed: 11686722]20. Gu XQ, Chen W, Morales-Morales D, Jensen CM. J Mol Cat A 2002;189:119–124.21. Diaz-Requejo, MMar; DiSalvo, D.; Brookhart, M. J Am Chem Soc 2003;125:2038. [PubMed:12590518]22. Lenges CP, Brookhart M, Grant BE. J Organometallic Chem 1997;528:199.Bolig and Brookhart Page 4J Am Chem Soc. Author manuscript; available in PMC 2008 November 28.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptFigure 1.Isostructural Late Metal Catalysts for Transfer HydrogenationBolig and Brookhart Page 5J Am Chem Soc. Author manuscript; available in PMC 2008 November 28.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptScheme 1.Bolig and Brookhart Page 6J Am Chem Soc. Author manuscript; available in PMC 2008 November 28.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptBolig and Brookhart Page 7Table 1Scope of enamine synthesis with 1 and 2SubstrateTransfer ProductCatat(h)Yield(%)b1342c6>902341>993561>9947812>9559101>95611121>9971314113813142c1>909151616d>901017181>951119201>95a Unless noted otherwise, 0.25 mmol substrate, 0.01 mmol 1 (4%), 0.5 mL C6D12, 80°C, 1h.J Am Chem Soc. Author manuscript; available in PMC 2008 November 28.NIH-PA Author ManuscriptNIH-PA Author ManuscriptNIH-PA Author ManuscriptBolig and Brookhart Page 8b By 1 H NMR spectroscopyc 0.25 mmol substrate, 0.01 mmol 2 (4%), 0.5 mL C6D12, 140°C. VDMS = Vinyl(DiMethyl)Silyl. EDMS = Ethyl(DiMethyl)Silyl.J Am Chem Soc. Author manuscript; available in PMC 2008 November 28.

Activation of sp 3 C−H Bonds with Cobalt(I): Catalytic Synthesis of Enamines

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