Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Oct 1;51(40):9980-92.
doi: 10.1002/anie.201202139. Epub 2012 Sep 11.

Silyl ketene imines: highly versatile nucleophiles for catalytic, asymmetric synthesis

Scott E Denmark  1 , Tyler W Wilson
Affiliations

Silyl ketene imines: highly versatile nucleophiles for catalytic, asymmetric synthesis

Scott E Denmark et al. Angew Chem Int Ed Engl. .

Abstract

This Minireview provides an overview on the development of silyl ketene imines and their recent applications in catalytic, enantioselective reactions. The unique structure of the ketene imine allows a diverse range of reactivity patterns and provides solutions to existing challenges in the enantioselective construction of quaternary stereogenic carbon centers and cross-benzoin adducts. A variety of reactions for which silyl ketene imines have been applied are presented with an overall goal of inspiring new uses for these underutilized nucleophiles.

PubMed Disclaimer

Figures

Scheme 1
Scheme 1
A) Synthesis of SKIs from nitriles yielding P and M enantiomers, where R1 >R2. B) Comparison to the synthesis of SKAs from esters yielding E and Z diastereomers.
Scheme 2
Scheme 2
A) Open transition state for a synclinal approach of an SKI to a Lewis acid activated aldehyde. B) Comparison to open transition state for synclinal approach of an SKA. LA = Lewis acid
Scheme 3
Scheme 3
Synthesis and spectroscopic data for SKI 5.
Scheme 4
Scheme 4
Synthesis of SKIs from disubstituted nitriles. LDA =lithium diisopropylamide, TBS =tert-butyldimethylsilyl, THF = tetrahydrofuran.
Scheme 5
Scheme 5
Competitive C silylation of monosubstituted nitriles.
Scheme 6
Scheme 6
Effect of chlorosilane on C versus N silylation of nitrile anions.
Scheme 7
Scheme 7
Stereoisomerization of N-aryl and N-alkyl ketene imines.
Scheme 8
Scheme 8
Aldol addition of SKI 10 to aromatic aldehydes.
Scheme 9
Scheme 9
Competitive 1,4- and 1,2-addition of SKI 10 with enals.
Scheme 10
Scheme 10
Addition of SKI 10 to ketones.
Scheme 11
Scheme 11
Uncatalyzed acylation of SKI 10 with acid halides.
Scheme 12
Scheme 12
Competitive N acylation of sterically hindered SKI 21.
Scheme 13
Scheme 13
Aldol addition of SKI 22 and subsequent Peterson elimination.
Scheme 14
Scheme 14
Oxidative decyanation of SKIs to afford ketone products.
Scheme 15
Scheme 15
Synthesis of N-silyl vinylketene imine from allyl cyanide.
Scheme 16
Scheme 16
[4+2] cycloaddition of N-silyl vinylketene imine 29.
Scheme 17
Scheme 17
Catalytic, enantioselective acylation of SKIs.
Scheme 18
Scheme 18
Catalytic, enantioselective aldol reaction of SKIs.
Scheme 19
Scheme 19
In situ generation of copper ketene imines and subsequent Mannich reaction.
Scheme 20
Scheme 20
Enantioselective Mannich reaction of SKIs.
Scheme 21
Scheme 21
Synthesis of substituted pyrrolidines using SKIs. Bz =benzoyl.
Scheme 22
Scheme 22
Catalytic, enantioselective conjugate addition of SKI 11.
Scheme 23
Scheme 23
Synthesis of N-silyl vinylketene imine 70.
Scheme 24
Scheme 24
Catalytic, enantioselective vinylogous addition of SKI 70.
Scheme 25
Scheme 25
Cyanide-catalyzed benzoin reaction.
Scheme 26
Scheme 26
In situ generation of metallo ketene imine 85 and subsequent enantioselective acylation.
Scheme 27
Scheme 27
N versus C silylation of protected cyanohydrin anions.
Scheme 28
Scheme 28
Synthesis of N-silyl oxyketene imines from tert-butyl-protected cyanohydrins.
Scheme 29
Scheme 29
Catalytic, enantioselective carbonyl additions of N-silyl oxyketene imines to aldehydes leading to either aldol products or cross-benzoin adducts depending on type of reaction quench.
Scheme 30
Scheme 30
Representative transformations of protected nitrile product 95. DIBAL =diisobutylaluminium hydride, PMB = para-methoxybenzyl.
See this image and copyright information in PMC

References

    1. Patai S. The Chemistry of Ketenes, Allenes and Related Compounds. Wiley; New York: 1980.
    2. Schuster HF, Coppola GM. Allenes in Organic Synthesis. Wiley; New York: 1984.
    3. Tidwell TT. Ketenes. Wiley; New York: 1995.
    1. Brownbridge P. Synthesis. 1983:1–28.
    2. Brownbridge P. Synthesis. 1983:85–104.
    3. Kita Y, Tamura O, Tamura Y. J Synth Org Chem Jpn. 1986;44:1118–1133.
    4. Kobayashi S, Manabe K, Ishitani H, Matsuo J-I. In: Science of Synthesis Organometallics: Silicon Compounds. Fleming I, Ley SV, editors. Vol. 4. Georg Thieme; Stuttgart: 2004. pp. 316–369.
    1. Narasaka K, Soai K, Mukaiyam T. Chem Lett. 1974:1223–1224.
    2. Oare DA, Heathcock CH. Top Stereochem. 1991;20:87–170.
    3. Oare DA, Heathcock CH. Top Stereochem. 1989;19:227–407.
    1. Mukaiyama T. Org React. 1982;28:203–331.
    2. Mukaiyama T, Banno K, Narasaka K. J Am Chem Soc. 1974;96:7503–7509.
    3. Mukaiyama T, Narasaka K, Banno K. Chem Lett. 1973:1011–1014.
    4. Mahrwald R. Modern Aldol Reactions. Wiley-VCH; Weinheim: 2004.
    1. Denissova I, Barriault L. Tetrahedron. 2003;59:10105–10146.
    2. Douglas CJ, Overman LE. Proc Natl Acad Sci USA. 2004;101:5363–5367. - PMC - PubMed
    3. Trost BM, Jiang C. Synthesis. 2006:369–396.
    4. Das JP, Marek I. Chem Commun. 2011;47:4593–4623. - PubMed
    5. Christoffers J, Baro A. Quaternary Stereocenters: Challenges and Solutions for Organic Synthesis. Wiley-VCH; Weinheim: 2005.

LinkOut - more resources