Skip to main content
Chemistry LibreTexts

6.2: Reactions of Ketones

  • Page ID
    168802
  • \( \newcommand{\vecs}[1]{\overset { \scriptstyle \rightharpoonup} {\mathbf{#1}} } \)

    \( \newcommand{\vecd}[1]{\overset{-\!-\!\rightharpoonup}{\vphantom{a}\smash {#1}}} \)

    \( \newcommand{\id}{\mathrm{id}}\) \( \newcommand{\Span}{\mathrm{span}}\)

    ( \newcommand{\kernel}{\mathrm{null}\,}\) \( \newcommand{\range}{\mathrm{range}\,}\)

    \( \newcommand{\RealPart}{\mathrm{Re}}\) \( \newcommand{\ImaginaryPart}{\mathrm{Im}}\)

    \( \newcommand{\Argument}{\mathrm{Arg}}\) \( \newcommand{\norm}[1]{\| #1 \|}\)

    \( \newcommand{\inner}[2]{\langle #1, #2 \rangle}\)

    \( \newcommand{\Span}{\mathrm{span}}\)

    \( \newcommand{\id}{\mathrm{id}}\)

    \( \newcommand{\Span}{\mathrm{span}}\)

    \( \newcommand{\kernel}{\mathrm{null}\,}\)

    \( \newcommand{\range}{\mathrm{range}\,}\)

    \( \newcommand{\RealPart}{\mathrm{Re}}\)

    \( \newcommand{\ImaginaryPart}{\mathrm{Im}}\)

    \( \newcommand{\Argument}{\mathrm{Arg}}\)

    \( \newcommand{\norm}[1]{\| #1 \|}\)

    \( \newcommand{\inner}[2]{\langle #1, #2 \rangle}\)

    \( \newcommand{\Span}{\mathrm{span}}\) \( \newcommand{\AA}{\unicode[.8,0]{x212B}}\)

    \( \newcommand{\vectorA}[1]{\vec{#1}}      % arrow\)

    \( \newcommand{\vectorAt}[1]{\vec{\text{#1}}}      % arrow\)

    \( \newcommand{\vectorB}[1]{\overset { \scriptstyle \rightharpoonup} {\mathbf{#1}} } \)

    \( \newcommand{\vectorC}[1]{\textbf{#1}} \)

    \( \newcommand{\vectorD}[1]{\overrightarrow{#1}} \)

    \( \newcommand{\vectorDt}[1]{\overrightarrow{\text{#1}}} \)

    \( \newcommand{\vectE}[1]{\overset{-\!-\!\rightharpoonup}{\vphantom{a}\smash{\mathbf {#1}}}} \)

    \( \newcommand{\vecs}[1]{\overset { \scriptstyle \rightharpoonup} {\mathbf{#1}} } \)

    \( \newcommand{\vecd}[1]{\overset{-\!-\!\rightharpoonup}{\vphantom{a}\smash {#1}}} \)

    \(\newcommand{\avec}{\mathbf a}\) \(\newcommand{\bvec}{\mathbf b}\) \(\newcommand{\cvec}{\mathbf c}\) \(\newcommand{\dvec}{\mathbf d}\) \(\newcommand{\dtil}{\widetilde{\mathbf d}}\) \(\newcommand{\evec}{\mathbf e}\) \(\newcommand{\fvec}{\mathbf f}\) \(\newcommand{\nvec}{\mathbf n}\) \(\newcommand{\pvec}{\mathbf p}\) \(\newcommand{\qvec}{\mathbf q}\) \(\newcommand{\svec}{\mathbf s}\) \(\newcommand{\tvec}{\mathbf t}\) \(\newcommand{\uvec}{\mathbf u}\) \(\newcommand{\vvec}{\mathbf v}\) \(\newcommand{\wvec}{\mathbf w}\) \(\newcommand{\xvec}{\mathbf x}\) \(\newcommand{\yvec}{\mathbf y}\) \(\newcommand{\zvec}{\mathbf z}\) \(\newcommand{\rvec}{\mathbf r}\) \(\newcommand{\mvec}{\mathbf m}\) \(\newcommand{\zerovec}{\mathbf 0}\) \(\newcommand{\onevec}{\mathbf 1}\) \(\newcommand{\real}{\mathbb R}\) \(\newcommand{\twovec}[2]{\left[\begin{array}{r}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\ctwovec}[2]{\left[\begin{array}{c}#1 \\ #2 \end{array}\right]}\) \(\newcommand{\threevec}[3]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\cthreevec}[3]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \end{array}\right]}\) \(\newcommand{\fourvec}[4]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\cfourvec}[4]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \end{array}\right]}\) \(\newcommand{\fivevec}[5]{\left[\begin{array}{r}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\cfivevec}[5]{\left[\begin{array}{c}#1 \\ #2 \\ #3 \\ #4 \\ #5 \\ \end{array}\right]}\) \(\newcommand{\mattwo}[4]{\left[\begin{array}{rr}#1 \amp #2 \\ #3 \amp #4 \\ \end{array}\right]}\) \(\newcommand{\laspan}[1]{\text{Span}\{#1\}}\) \(\newcommand{\bcal}{\cal B}\) \(\newcommand{\ccal}{\cal C}\) \(\newcommand{\scal}{\cal S}\) \(\newcommand{\wcal}{\cal W}\) \(\newcommand{\ecal}{\cal E}\) \(\newcommand{\coords}[2]{\left\{#1\right\}_{#2}}\) \(\newcommand{\gray}[1]{\color{gray}{#1}}\) \(\newcommand{\lgray}[1]{\color{lightgray}{#1}}\) \(\newcommand{\rank}{\operatorname{rank}}\) \(\newcommand{\row}{\text{Row}}\) \(\newcommand{\col}{\text{Col}}\) \(\renewcommand{\row}{\text{Row}}\) \(\newcommand{\nul}{\text{Nul}}\) \(\newcommand{\var}{\text{Var}}\) \(\newcommand{\corr}{\text{corr}}\) \(\newcommand{\len}[1]{\left|#1\right|}\) \(\newcommand{\bbar}{\overline{\bvec}}\) \(\newcommand{\bhat}{\widehat{\bvec}}\) \(\newcommand{\bperp}{\bvec^\perp}\) \(\newcommand{\xhat}{\widehat{\xvec}}\) \(\newcommand{\vhat}{\widehat{\vvec}}\) \(\newcommand{\uhat}{\widehat{\uvec}}\) \(\newcommand{\what}{\widehat{\wvec}}\) \(\newcommand{\Sighat}{\widehat{\Sigma}}\) \(\newcommand{\lt}{<}\) \(\newcommand{\gt}{>}\) \(\newcommand{\amp}{&}\) \(\definecolor{fillinmathshade}{gray}{0.9}\)

    Enantioselective reduction of C=O double bond in organic synthesis has important application in synthesis of many natural products as well as pharmaceutical products. The lecture covers the representative examples of metal catalyzed reactions. The reactions using CBS and enzymes are covered in the other modules of this course. The frequently used chiral ligands for the metal catalyzed enantioselective reduction reactions of ketones are listed in Scheme \(\PageIndex{1}\).

    clipboard_eb65ffae3f5eac8c80cc365b9cff49776.png
    Scheme \(\PageIndex{1}\)

    6.2.1 Reactions of α-Keto Amides

    Asymmetric hydrogenation of α -keto esters has been studied with several rhodium catalysts. Neutral rhodium catalysts with chiral ligands such as Cr(CO)3-Cp,Cp-Indo-NOP demonstrate excellent enantioselectivity and reactivity in the hydrogenation of amides (Scheme \(\PageIndex{2}\)).

    clipboard_e5f562c94739abf204986f60046bdfeb0.png
    Scheme \(\PageIndex{2}\): Enantioselective Hydrogenation of α -Keto Amide

    6.2.2 Reactions of β - Keto Esters

    Asymmetric hydrogenation of β -keto esters has been extensively studied using chiral ruthenium catalysts. However, only handful of examples analogous to rhodium-catalyzed reaction are explored (Scheme 3). The Rh-( R,S )-Josiphos complex provides an effective catalyst for the asymmetric hydrogenation of ethyl 3-oxobutanoate affording the corresponding β -hydroxy ester in 97% ee. The above ligands Josiphos family such as chiral Walphos, Joshiphos, BPPFOH, TRAP and PIGIPHOS ligands could be easily synthesized from commercially available Ugi amine (Scheme \(\PageIndex{4}\)-\(\PageIndex{6}\)).

    clipboard_e3962b90816054135204da7bf9fe07fff.png
    Scheme \(\PageIndex{3}\): Enantioselective Hydrogenation of β -Keto ester
    clipboard_ef581b98f1d7448a34cfc88bea10b1945.png
    Scheme \(\PageIndex{4}\): Synthesis of Josiphos Type Ligands
    clipboard_e4b40ea50e5a52b93451d83db98c001a5.png
    Scheme \(\PageIndex{5}\): Synthesis of Feluphos
    clipboard_e9fe9aa19d17255f21f0a6b8d8bff95c5.png
    Scheme \(\PageIndex{6}\): Synthesis of Taniaphos

    Iridium/spiro PAP has been used as effective catalyst for the asymmetric hydrogenation of β-aryl β-ketoesters (Scheme \(\PageIndex{7}\)). The reaction provides a readily accessible method for the synthesis of β-hydroxy esters in high enantioselectivity up to 99.8% ee and high TONs up to 1230000.

    clipboard_e463f43006cb56be6372872ac603419d8.png
    Scheme \(\PageIndex{7}\): Enantioselective hydrogenation of β- ketoesters

    6.2.3 Reactions of Aromatic Ketones

    Amino ketones and their hydrochloride salts can be effectively hydrogenated with chiral rhodium catalysts (Scheme \(\PageIndex{8}\)). The rhodium precatalysts, combined with chiral phosphorous ligands (S,S)- MCCPM provide excellent enantioselectivity and reactivity for the asymmetric hydrogenation of α, β, and γ -alkyl amino ketone hydrochloride salts with S/C=100000.

    clipboard_ea8f18a3f148496b23466d58de87084e6.png
    Scheme \(\PageIndex{8}\): Enantioselective Hydrogenation of α -Aryl Amino Ketone

    The enantioselective hydrogenation of 3,5-bistrifluoromethyl acetophenone (BTMA) can be carried out using a Ru/phosphine-oxazoline complex (Scheme \(\PageIndex{9}\)) . The reaction is compatible with 140-kg scale at 20 bar and 25°C with S/C ratios of 20,000. The synthesis of the ligand is shown in Scheme \(\PageIndex{10}\).

    clipboard_e3bb66317be9ef7e736825f553de3bf54.png
    Scheme \(\PageIndex{9}\): Hydrogenation of α -Aryl Ketone
    clipboard_e9e0a3071ba9144c42d8ed7613c94e595.png
    Scheme \(\PageIndex{10}\): Synthesis of (S,Sp)- 1,2-P,N-Ferrocine

    The enantioselective hydrogenation of amino ketones has been applied extensively to the synthesis of chiral drugs and pharmaceuticals (Scheme \(\PageIndex{11}\)). For example, direct enantioselective hydrogenation of 3-aryloxy-2-oxo-1-propylamine leads to 1-amino-3-aryloxy-2-propanol using 0.01 mol % of the neutral Rh-(S, S)-MCCPM complex. The chiral product 1-amino-3-aryloxy-2-propanol serves as β-adrenergic blocking agents. (S)-Propranolol is obtained in 90.8% ee from the corresponding α-amino ketone.

    clipboard_e62041d017d7dbabf2f3f4dce71b89504.png
    Scheme \(\PageIndex{11}\): Key step for the Direct Synthesis of (S)- Propranolol
    clipboard_ec67c9fed4acbc6946a88b66a7ebd7474.png
    Scheme \(\PageIndex{12}\): Asymmetric Reduction of Acetophenone

    6.2.4 Reactions of Aliphatic Ketones

    The asymmetric hydrogenation of simple aliphatic ketones remains still a challenging problem. This is due to the difficulty to design the appropriate chiral catalyst that will easily differentiate between the two-alkyl substituents of the ketone. Promising results have been obtained in asymmetric hydrogenation of aliphatic ketones using the ( R,S,R,S )-PennPhos- Rh complex in combination with 2,6-lutidine and KBr. For example, the reaction of tert -butyl methyl ketone takes place with 94% ee . Similarly, isopropyl-, n -butyl- and cyclohexyl methyl ketones can be reduced with 85% ee , 75% ee and 92% ee, respectively.

    clipboard_eae22b2021605d1f39d2f8d643fe14a1a.png
    Scheme \(\PageIndex{13}\)

    The chiral Ru-diphosphine/diamine derived from chiral BINAP, DPEN (diphenylethylene diamine) and indanol effect enantioselective hydrogenation of certain amino or amido ketones via a non-chelate mechanism without interaction between Ru and nitrogen or oxygen (Scheme \(\PageIndex{14}\)). The diamine catalyst can be synthesized from chiral 1,2- diphenylethylene diamine (Scheme \(\PageIndex{15}\)).

    clipboard_e111f8f36bda81f3779725a408d988703.png
    Scheme \(\PageIndex{14}\)
    clipboard_ea2d6da215ac75c3dc659c51b63c59bb2.png
    Scheme \(\PageIndex{15}\)

    These catalysts have been employed for the asymmetric synthesis of various important pharmaceuticals, including (R)-denopamine, a β 1-receptor agonist, the anti -depressant (R)-fluoxetine, the anti -psychotic BMS 181100 and (S)-duloxetine (Scheme \(\PageIndex{16}\)).

    clipboard_eb7a4b0499e4def6706927ac57c926c56.png
    Scheme \(\PageIndex{16}\)

    Unsymmetric benzophenones could also be hydrogenated with high S/C ratio of up to 20000 without over-reduction (Scheme \(\PageIndex{17}\)). Enantioselective hydrogenation of certain ortho -substituted benzophenones leads to the unsymmetrically substituted benzhydrols, allowing convenient synthesis of the anti- cholinergic and anti -histaminic (S)-orphenadrine and antihistaminic (R)-neobenodine.

    clipboard_e717a867c01d0491838f89c0626ce6d61.png
    Scheme \(\PageIndex{17}\): Asymmetric Synthesis of Some of the Important Pharmaceuticals

    The asymmetric hydrogenation of simple ketone is generally achieved by the combined use of an (S)-BINAP and an (S)-1,2-diphenylethylenediamine. However, the reaction of 2,4,4-trimethyl-2-cyclohexenone can be effectively done with racemic RuCl2 [-tol-BINAP]- and chiral DPEN with up to >95% ee (Scheme \(\PageIndex{18}\)).

    clipboard_e73c1746cf8b6da15a5d534541dcf27eb.png
    Scheme \(\PageIndex{18}\)

    This page titled 6.2: Reactions of Ketones is shared under a CC BY-SA license and was authored, remixed, and/or curated by Tharmalingam Punniyamurthy (National Programme on Technology Enhanced Learning (NPTEL) ) .

    • Was this article helpful?