Synlett 2013; 24(1): 1-5
DOI: 10.1055/s-0032-1317684
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© Georg Thieme Verlag Stuttgart · New York

Ketone-Based Transition-Metal-Catalyzed Carbon–Carbon and Carbon– Hydrogen Bond Activation: Exploratory Studies

Guangbin Dong*
  • Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX 78712, USA   Fax: +1(512)4710397   Email: gbdong@cm.utexas.edu
Further Information

Publication History

Received: 12 September 2012

Accepted after revision: 01 November 2012

Publication Date:
27 November 2012 (eFirst)

 

Dedicated to Professor Barry M. Trost

Abstract

The importance and ubiquity of ketone functional groups in organic synthesis has always been a driving force for discovering new modes of reactivity. Stimulated by the challenges of fused-ring synthesis and ketone alkylation, we summarize here our exploratory studies on ketone-based transition-metal-catalyzed carbon–carbon and carbon–hydrogen bond activation.


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Ketones are among the most important and ubiquitous functional groups found in a diversity of molecules ranging from natural products to materials. They also serve as key intermediates for many transformations in organic chemistry.[ 1 ] Selective reactions mediated by ketones have made a significant impact on organic synthesis in the past. Most of these reactions are generally driven by either the electrophilic character of the carbonyl carbon or the acidity of the α-hydrogen (Scheme [1]). Thus, methodologies based on new modes of reactivity of ketones, particularly those that can provide high atom-economy,[ 2 ] are important and highly sought after.

Our research has been inspired by two long-standing ketone-related synthetic challenges: (1) finding a unified strategy to access fused rings using simple cyclic ketones as precursors and (2) the alkylation of ketones using simple unactivated olefins. Here, we summarize our recent progress towards these goals using transition-metal-catalyzed carbon–carbon and carbon–hydrogen bond functionalization.

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Scheme 1 General reactivity of ketones

Ketone-Based Carbon–Carbon Bond Activation

Fused ring systems are widely found in natural products and drugs. Aiming towards a unified strategy for their synthesis, we conceived a catalytic ‘cut and sew’ approach using simple cyclic ketones as precursors (Scheme [2]).[ 3 ] In this approach, the transition-metal catalyst first ‘cuts’ the α-carbon–carbon bond of the ketone through oxidative addition, and then ‘sews’ to give fused rings via the migratory insertion of an unsaturated unit followed by reductive elimination. It is expected that by changing ring sizes, linker lengths, and unsaturated unit types, a great diversity of fused-ring scaffolds, which are difficult to access by conventional methods, will be afforded using a single approach.

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Guangbin Dongreceived his B.S. degree from Peking University and completed his Ph.D. degree in chemistry at Stanford University, where he was a Larry Yung Stanford Graduate Fellow working with Professor Barry M. Trost. In 2009, he began research with Professor Robert H. Grubbs at the California Institute of Technology as a Camille and Henry Dreyfus Environmental Chemistry Fellow. In 2011, he joined the Department of Chemistry and Biochemistry at the University of Texas at Austin as an assistant professor and a CPRIT (Cancer Prevention Research Institute of Texas) Scholar. His research interests lie in the development of powerful chemical tools for addressing questions of biological importance.
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Scheme 2 A ‘cut and sew’ strategy for the synthesis of fused rings

To prove the feasibility of this ‘cut and sew’ strategy, we initially focused on a benzocyclobutenone system. Also known as ‘vinylketene’ equivalents, cyclobutenones can undergo ring opening followed by the insertion of alkenes or alkynes under thermal conditions (Scheme [3]).[ 4 ] Higher reactivity and a broader scope have been shown using transition-metal catalysts. Pioneering work by Huffman and Liebeskind demonstrated that the insertion of alkynes into cyclobutenones can be catalyzed using a nickel catalyst.[ 5 ] Contributions from Kondo and Mitsudo and co-workers enabled electron-deficient olefins norbornene and ethene to react intermolecularly using rhodium or ruthenium as catalysts.[ 6 ] Decarbonylative insertions have also been developed.[ 7 ] More recently, the insertion of alkynylboronates into cyclobutenones has been reported by Auvinet and Harrity.[ 8 ] It is noteworthy that in these transformations, cleavage of the less-hindered C-1–C-8 bond is generally observed.

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Scheme 3 Carbon–carbon bond cleavage of cyclobutenones

The intramolecular version of the aforementioned transformation was also reported by South and Liebeskind, where a cobalt-mediated cyclization occurred between a benzocyclobutenedione and an alkyne. This method has been utilized in the total synthesis of nanaomycin A (Scheme [4], part a).[ 9 ] Seminal work by Murakami et al. illustrated the catalytic intramolecular insertion of styrene-type olefins into cyclobutanones to give bridged ring systems, where complementary reaction pathways were achieved using different catalysts (Scheme [4], part b).[ 10 ]

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Scheme 4 Seminal examples of intramolecular cyclization; cod = cycloocta-1,5-diene; nbd = norbornadiene; dppp = 1,3-bis(diphenylphosphino)propane; BHT = butylated hydroxytoluene

We recently developed an olefin-directed, rhodium-catalyzed carboacylation using benzocyclobutenones, in which the more-hindered C-1–C-2 bonds are selectively activated (Scheme [5]).[ 3 ] A broad range of olefins can undergo this ‘cut and sew’ sequence including mono-, di-, and even trisubstituted olefins with both alkyl or aryl substituents. In addition, all-carbon quaternary centers can be efficiently generated and a number of functional groups are tolerated under the reaction conditions.

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Scheme 5 ‘Cut and sew’ to access fused rings; dppb = 1,4-bis(diphenylphosphino)butane; brsm = based on recovered starting material

Furthermore, Lewis acid catalysts, such as zinc(II) chloride, were found to greatly enhance the overall reactivity; its usage was critical for more-challenging substrates, such as trisubstituted olefins and those that form hydropyran rings. We postulate that the role of the Lewis acid, zinc(II) chloride, in this catalytic cycle is twofold: it promotes both oxidative addition and reductive elimination through coordination with the carbonyl group of the substrate and the rhodacycle intermediate, respectively. This interaction makes both the substrate and the rhodacycle intermediate electron deficient.[ 3 ] The proposed catalytic cycle is depicted in Scheme [6].

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Scheme 6 Proposed catalytic cycle

We expect this carbon–carbon bond activation method to serve as an important preliminary study towards our long-term goal of developing a unified strategy for fused-ring synthesis.

Ketone-Based Carbon–Hydrogen Bond Activation

As one of the most significant ways to generate carbon–carbon bonds, the alkylation of ketones has had long-standing interest.[ 11 ] Classical ways to alkylate ketones generally require strong bases (such as LDA) and halogen-based agents (Scheme [7], part a). The formation of stoichiometric byproducts and the difficulty associated in controlling monoalkylation/regioselectivity have been concerns using such reactions.[ 12 ] The Stork enamine reaction is considered a breakthrough for the alkylation of ketones owing to its excellent regioselectivity and obviation of multiple alkylations (Scheme [7], part b); however, reactive alkylating agents are generally needed (i.e., methyl or allylic halides or Michael acceptors).[ 13 ]

In search for a ‘green’ method to prepare alkylated ketones, we have been intrigued by the idea of using ‘simple unactivated olefins’ as alkylating agents through catalytic carbon–hydrogen bond and olefin coupling.

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Scheme 7 Classical methods for ketone alkylation

Intramolecular coupling between ketones and unactivated olefins has been well documented as the Conia-ene reaction.[ 14 ] Generally, this reaction proceeds at high temperatures (>250 °C) and with moderate yields, and only a few functional groups are tolerated under the reaction conditions. Further seminal work on catalytic intramolecular cyclizations by Toste and co-workers[ 15 ] and others[16] [17] involves Lewis acid metal-catalyzed coupling of activated methylene groups with alkynes. In addition, an intramolecular palladium-catalyzed ketone addition to olefins for accessing various cyclohexanone derivatives was first reported by Widenhoefer.[ 18 ] Fewer efforts have been made on catalytic intermolecular ketone–olefin couplings. A potassium tert-butoxide catalyzed addition of ketones to styrenes was developed by Knochel and co-workers,[ 19 ] and a manganese/cobalt-initiated radical process for the addition of ketones across nonaromatic olefins was reported by Ishii and co-workers, albeit requiring a large excess of ketone.[ 20 ] Hence, a general method for the addition of ketone α-carbon–hydrogen bonds across olefins remains underdeveloped.

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Scheme 8 A proposed strategy for ketone–olefin coupling
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Scheme 9 Regioselective C-alkylation of cyclic 1,2-diketones

Inspired by the Stork enamine reaction, we conceived a carbon–hydrogen bond functionalization strategy to achieve the desired ketone–olefin coupling. We envisaged that enamine formation would convert the ketone α-sp3-carbon–hydrogen bonds into sp2-carbon–hydrogen ones, thus enhancing their reactivity towards oxidative addition by a low-valent transition metal (Scheme [8]). Meanwhile, if we incorporated a proper directing group (DG) in the amine agent, metalation would be directed to the α-carbon–hydrogen bonds upon enamine formation.[ 21 ] Subsequent olefin insertion–reductive elimination and enamine hydrolysis would lead to the desired α-alkylation product. As documented in organocatalysis, enamine formation and hydrolysis can exist in an equilibrium, but the less-hindered ketone (starting material) forms the enamine faster than the hindered ketone (product).[ 22 ] In addition, such an equilibrium is known to be compatible with the rhodium-catalyzed carbon–hydrogen bond/olefin coupling reaction.[ 23 ] Therefore, in principle, the amine DG can be employed catalytically.

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Scheme 10 C-Alkylation of cyclic 1,2-diketones through enamine formation

Serving as an important proof of concept, we recently demonstrated the feasibility of such a strategy for a 1,2-diketone system (Scheme [9]).[ 24 ] 2-Aminopyridine was employed as a traceless and removable DG.[ 25 ] Delightfully, after exploration of the reaction conditions, the desired enamine formation and subsequent carbon–hydrogen bond/olefin coupling proceed smoothly (Scheme [10]). A range of terminal olefins undergo the coupling reaction providing the desired alkylated enamines in low to good yields.

Further, we also demonstrated the DG can be removed and recycled, providing the monoalkylated diketone (Scheme [11], part a). Finally, the enamine formation, carbon–hydrogen bond/olefin coupling, and hydrolysis can all be operated in one pot (Scheme [11], part b). The efficiency of this method is also demonstrated in the synthesis of a natural flavoring compound (from roasted coffee), 3-ethyl-5-methylcyclopenta-1,2-dione (one pot, 53% vs 16% yield from a previous route of 4 steps from the same starting material).[ 26 ] We expect that this work will serve as a seminal study towards catalytic ketone α-alkylation with unactivated olefins.

In conclusion, our exploratory studies towards ketone-based carbon–carbon and carbon–hydrogen bond activation have been summarized. These include a ‘cut and sew’ strategy to prepare fused rings and a dual-activation strategy[ 27 ] for ketone alkylation using simple olefins. Although still in the very preliminary stage, efforts in these arenas should have a broad impact on the enhancement of synthetic efficiency.

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Scheme 11 Removal of the directing group and the one-pot reaction

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Acknowledgment

We thank UT Austin and CPRIT for a start-up fund, and we thank the Welch Foundation and Frasch Foundation for research grants. G.D. thanks Oak Ridge Associated Universities (ORAU) for a new faculty enhancement award. We also thank faculty members from the organic division at UT Austin for their generous support. Johnson Matthey is thanked for the Rh salts. Chiral Technologies is thanked for their kind donation of chiral high-performance liquid chromatography columns.

  • References

  • 1 Modern Carbonyl Chemistry . Otera J. Wiley-VCH; Weinheim; 2000
  • 2 Trost BM. Science (Washington, DC, U.S.) 1991; 254: 1471
  • 3 Xu T, Dong G. Angew. Chem. Int. Ed. 2012; 51: 7567
    • 4a Danheiser RL, Gee SK. J. Org. Chem. 1984; 49: 1672
    • 4b Schiess P, Eberle M, Huys-Francotte M, Wirz J. Tetrahedron Lett. 1984; 25: 2201
  • 5 Huffman MA, Liebeskind LS. J. Am. Chem. Soc. 1991; 113: 2771
    • 6a Kondo T, Taguchi Y, Kaneko Y, Niimi M, Mitsudo T. Angew. Chem. Int. Ed. 2004; 43: 5369
    • 6b Kondo T, Niimi M, Nomura M, Wada K, Mitsudo T. Tetrahedron Lett. 2007; 48: 2837

      For recent reviews, see:
    • 7a Kondo T. Synlett 2008; 629
    • 7b Kondo T, Mitsudo T. Chem. Lett. 2005; 34: 1462
  • 8 Auvinet A-L, Harrity JP. A. Angew. Chem. Int. Ed. 2011; 50: 2769
  • 9 South MS, Liebeskind LS. J. Am. Chem. Soc. 1984; 106: 4181
    • 10a Murakami M, Itahashi T, Ito Y. J. Am. Chem. Soc. 2002; 124: 13976
    • 10b Murakami M, Ashida S. Chem. Commun. (Cambridge) 2006; 4599
  • 11 Cain D In Carbon-Carbon Bond Formation . Vol. 1. Augustine RL. Marcel Dekker; New York; 1979: 85
  • 12 Smith MB, March J. March’s Advanced Organic Chemistry 2001
    • 13a Stork G, Terrell R, Szmuszkovicz JA. J. Am. Chem. Soc. 1954; 76: 2029
    • 13b Stork G, Landesman H. J. Am. Chem. Soc. 1956; 78: 5128
  • 14 Conia JM, Le Perchec P. Synthesis 1975; 1
  • 15 Kennedy-Smith JJ, Staben ST, Toste FD. J. Am. Chem. Soc. 2004; 126: 4526
  • 16 Chan LY, Kim S, Park Y, Lee PH. J. Org. Chem. 2012; 77: 5239 ; and references cited therein
  • 17 Dénès F, Pérez-Luna A, Chemla F. Chem. Rev. 2010; 110: 2366
    • 18a Pei T, Widenhoefer RA. J. Am. Chem. Soc. 2001; 123: 11290
    • 18b Widenhoefer RA. Pure Appl. Chem. 2004; 76: 671
  • 19 Rodriguez AL, Bunlaksananusorn T, Knochel P. Org. Lett. 2000; 2: 3285
  • 20 Iwahama T, Sakaguchi S, Ishii Y. Chem. Commun. (Cambridge) 2000; 2317

    • For reviews on removable DGs, see:
    • 21a Rousseau G, Breit B. Angew. Chem. Int. Ed. 2011; 50: 2450
    • 21b Tan KL. Nat. Chem. 2012; 4: 253
    • 22a MacMillan DW. C. Nature (London) 2008; 455: 304
    • 22b List B. Chem. Rev. 2007; 107: 5413
  • 23 Jun C.-H, Moon CW, Kim Y.-M, Lee H, Lee JH. Tetrahedron Lett. 2002; 43: 4233
  • 24 Wang Z, Reinus BJ, Dong G. J. Am. Chem. Soc. 2012; 134: 13954

    • Aminopyridines have been used in aldehyde carbon–hydrogen bond activation; for seminal work and a review, see:
    • 25a Suggs JW. J. Am. Chem. Soc. 1979; 101: 489
    • 25b Jun C.-H, Moon CW, Lee D.-Y. Chem.–Eur. J. 2002; 8: 2423
  • 26 Nishimura O, Mihara S. J. Agric. Food Chem. 1990; 38: 1038

    • For reviews, see:
    • 27a Zhong C, Shi X. Eur. J. Org. Chem. 2010; 2999
    • 27b Allen AE, MacMillan DW. C. Chem. Sci. 2012; 3: 633

  • References

  • 1 Modern Carbonyl Chemistry . Otera J. Wiley-VCH; Weinheim; 2000
  • 2 Trost BM. Science (Washington, DC, U.S.) 1991; 254: 1471
  • 3 Xu T, Dong G. Angew. Chem. Int. Ed. 2012; 51: 7567
    • 4a Danheiser RL, Gee SK. J. Org. Chem. 1984; 49: 1672
    • 4b Schiess P, Eberle M, Huys-Francotte M, Wirz J. Tetrahedron Lett. 1984; 25: 2201
  • 5 Huffman MA, Liebeskind LS. J. Am. Chem. Soc. 1991; 113: 2771
    • 6a Kondo T, Taguchi Y, Kaneko Y, Niimi M, Mitsudo T. Angew. Chem. Int. Ed. 2004; 43: 5369
    • 6b Kondo T, Niimi M, Nomura M, Wada K, Mitsudo T. Tetrahedron Lett. 2007; 48: 2837

      For recent reviews, see:
    • 7a Kondo T. Synlett 2008; 629
    • 7b Kondo T, Mitsudo T. Chem. Lett. 2005; 34: 1462
  • 8 Auvinet A-L, Harrity JP. A. Angew. Chem. Int. Ed. 2011; 50: 2769
  • 9 South MS, Liebeskind LS. J. Am. Chem. Soc. 1984; 106: 4181
    • 10a Murakami M, Itahashi T, Ito Y. J. Am. Chem. Soc. 2002; 124: 13976
    • 10b Murakami M, Ashida S. Chem. Commun. (Cambridge) 2006; 4599
  • 11 Cain D In Carbon-Carbon Bond Formation . Vol. 1. Augustine RL. Marcel Dekker; New York; 1979: 85
  • 12 Smith MB, March J. March’s Advanced Organic Chemistry 2001
    • 13a Stork G, Terrell R, Szmuszkovicz JA. J. Am. Chem. Soc. 1954; 76: 2029
    • 13b Stork G, Landesman H. J. Am. Chem. Soc. 1956; 78: 5128
  • 14 Conia JM, Le Perchec P. Synthesis 1975; 1
  • 15 Kennedy-Smith JJ, Staben ST, Toste FD. J. Am. Chem. Soc. 2004; 126: 4526
  • 16 Chan LY, Kim S, Park Y, Lee PH. J. Org. Chem. 2012; 77: 5239 ; and references cited therein
  • 17 Dénès F, Pérez-Luna A, Chemla F. Chem. Rev. 2010; 110: 2366
    • 18a Pei T, Widenhoefer RA. J. Am. Chem. Soc. 2001; 123: 11290
    • 18b Widenhoefer RA. Pure Appl. Chem. 2004; 76: 671
  • 19 Rodriguez AL, Bunlaksananusorn T, Knochel P. Org. Lett. 2000; 2: 3285
  • 20 Iwahama T, Sakaguchi S, Ishii Y. Chem. Commun. (Cambridge) 2000; 2317

    • For reviews on removable DGs, see:
    • 21a Rousseau G, Breit B. Angew. Chem. Int. Ed. 2011; 50: 2450
    • 21b Tan KL. Nat. Chem. 2012; 4: 253
    • 22a MacMillan DW. C. Nature (London) 2008; 455: 304
    • 22b List B. Chem. Rev. 2007; 107: 5413
  • 23 Jun C.-H, Moon CW, Kim Y.-M, Lee H, Lee JH. Tetrahedron Lett. 2002; 43: 4233
  • 24 Wang Z, Reinus BJ, Dong G. J. Am. Chem. Soc. 2012; 134: 13954

    • Aminopyridines have been used in aldehyde carbon–hydrogen bond activation; for seminal work and a review, see:
    • 25a Suggs JW. J. Am. Chem. Soc. 1979; 101: 489
    • 25b Jun C.-H, Moon CW, Lee D.-Y. Chem.–Eur. J. 2002; 8: 2423
  • 26 Nishimura O, Mihara S. J. Agric. Food Chem. 1990; 38: 1038

    • For reviews, see:
    • 27a Zhong C, Shi X. Eur. J. Org. Chem. 2010; 2999
    • 27b Allen AE, MacMillan DW. C. Chem. Sci. 2012; 3: 633

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Scheme 1 General reactivity of ketones
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Guangbin Dongreceived his B.S. degree from Peking University and completed his Ph.D. degree in chemistry at Stanford University, where he was a Larry Yung Stanford Graduate Fellow working with Professor Barry M. Trost. In 2009, he began research with Professor Robert H. Grubbs at the California Institute of Technology as a Camille and Henry Dreyfus Environmental Chemistry Fellow. In 2011, he joined the Department of Chemistry and Biochemistry at the University of Texas at Austin as an assistant professor and a CPRIT (Cancer Prevention Research Institute of Texas) Scholar. His research interests lie in the development of powerful chemical tools for addressing questions of biological importance.
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Scheme 2 A ‘cut and sew’ strategy for the synthesis of fused rings
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Scheme 3 Carbon–carbon bond cleavage of cyclobutenones
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Scheme 4 Seminal examples of intramolecular cyclization; cod = cycloocta-1,5-diene; nbd = norbornadiene; dppp = 1,3-bis(diphenylphosphino)propane; BHT = butylated hydroxytoluene
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Scheme 5 ‘Cut and sew’ to access fused rings; dppb = 1,4-bis(diphenylphosphino)butane; brsm = based on recovered starting material
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Scheme 6 Proposed catalytic cycle
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Scheme 7 Classical methods for ketone alkylation
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Scheme 8 A proposed strategy for ketone–olefin coupling
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Scheme 9 Regioselective C-alkylation of cyclic 1,2-diketones
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Scheme 10 C-Alkylation of cyclic 1,2-diketones through enamine formation
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Scheme 11 Removal of the directing group and the one-pot reaction