Elsevier

Tetrahedron

Volume 60, Issue 22, 24 May 2004, Pages 4837-4860
Tetrahedron

Dibromomethane as one-carbon source in organic synthesis: a versatile methodology to prepare the cyclic and acyclic α-methylene or α-keto acid derivatives from the corresponding terminal alkenes

Dedicated to Professor Teh-Chang Chou of National Chung Cheng University on the occasion of his 60th birthday
https://doi.org/10.1016/j.tet.2004.04.013Get rights and content

Abstract

Ozonolysis of mono-substituted alkenes A-1 followed by reacting with a preheated mixture of CH2Br2–Et2NH affords α-substituted acroleins A-2 in good yields. Under very mild reaction conditions, these α-substituted acroleins A-2 can be easily converted to α-methylene esters A-4, which could be further converted to the corresponding α-keto esters A-5. This methodology can be also applied to the preparation of α-methylene lactones B-4, α-methylene lactams, and α-keto lactones B-5 with various ring sizes.

Introduction

In the previous studies, the ozonide 2 or aldehyde 3 was treated with a preheated mixture of CH2Br2 and Et2NH to give the acrolein 4 in modest to good yields (Eqs. , )1 whilst the aryl alkyl ketone 5 reacted with a mixture of CH2Br2 and Et2NH under microwave condition to give the corresponding α-methylene ketone 6 (Eq. 3).2 The β-carbon of the conjugated carbonyl compound was derived from CH2Br2. In comparison with similar transformation reported in the literature,3., 4., 5. the characteristic features of our methodology are described as follows. Both CH2Br2 and Et2NH are cheap. Their salts can be easily prepared in situ and used in the same flask to carry out the α-methylenation. The reaction was carried out in nonaqueous media under mild reaction condition. In addition, both ozonide and aldehyde can be converted to the desired product. Therefore, a preheated mixture of CH2Br2 and Et2NH is a convenient and economic reagent as one-carbon synthetic equivalent in organic synthesis.α-Methylene-γ-butyrolactone is an important moiety in several biological active compounds. Therefore, the development of their preparative methodologies has been attractive to many synthetic organic chemists.6., 7., 8., 9., 10., 11., 12., 13., 14., 15., 16., 17., 18., 19. However, there are only few reports to describe the preparation of α-methylene-β-propiolactones20., 21. and α-methylene-δ-valerolactones.22., 23. To the best of our knowledge, there is no general strategy which can be useful to prepare 4- to 7-memebred ring α-methylene lactones.24 α-Keto acid derivatives play important roles not only in organic synthesis but also in biologically active natural products.25., 26. The preparation of the α-keto acid was categorized as the following. Oxidation of α-hydroxy esters or their equivalents,27a–c oxidative cleavage of the double bond of α,β-unsaturated carbonyl compounds,27d,e α-oxidation of carbonyl groups,27f and metal-catalyzed double carbonylation27g are typical methods to prepare α-keto acid derivatives.27 Likewise, α-keto amides are mostly obtained from amidation of α-hydroxy esters or acids, followed by oxidation. Of the above methods, most lack generality or suffer from lengthy procedures. The use of toxic KCN and drastic hydrolytic conditions limit the application of some methods for the preparation of α-keto acid derivatives with labile functional groups.27a–c

In our previous report, we described a methodology to prepare the α-methylene acid or α-keto acid derivatives from the corresponding terminal alkenes. The α-methylene group is a masked form of carbonyl group. The α-substituted acroleins were proved to be the suitable precursors to the formation of α-keto acid derivatives.28 Its retrosynthetic analysis was described in Figure 1. The α,β-unsaturated carboxylic acid A-3 would be prepared from the mild oxidation of the α,β-unsaturated aldehyde A-2, which would be derived easily from terminal alkene A-1 by our reaction condition as shown in Eq. 1. The methyl acrylate A-4 would be a reasonable precursor to the α-keto acid ester A-5. By using similar methodology, the hydroxy-alkene B-1 would be a reasonable starting material for the preparation of α-methylene lactone B-4 and α-keto lactone B-5. The ring size of the lactone is dependent on the chain length of the spacer between the hydroxy and alkene moieties of compound B (Fig. 1). In this report, we shall describe our effort in the synthesis of acyclic and cyclic α-methylene acid derivatives and their α-keto acid derivatives in detail.

Section snippets

Preparation of acyclic α-methylene acids and their α-keto acid derivatives from the corresponding terminal alkenes

The ozonolysis of 1-decene (1a) followed by addition of a preheated mixture of CH2Br2 and Et2NH afforded acrolein 4a in 62% yield. The oxidation of acroleins to methyl acrylates by MnO2 in the presence of KCN in methanol has been reported in high yield.29 In order to avoid using toxic KCN, we tried to use other reagents. The oxidation of α-substituted acrolein 4a by Jones reagent gave an inseparable mixture of the acrylic acid 7a in addition to an over-oxidized product. We found that a modified

Conclusions

In summary, we have developed a general methodology to prepare the acyclic α-substituted acrylic acids and their derivatives from the corresponding terminal alkenes. The further cleavage of their α-methylene groups by the ozonolysis gave the corresponding α-keto acid derivatives in good yields. The reaction conditions in each step are quite mild that substrates with labile functional groups can be used. This methodology can also be applied to prepare 4- to 7-membered ring α-methylene lactones

Experimental

All reactions were carried out under nitrogen. Unless otherwise noted, materials were obtained from commercial suppliers and used without further purification. Melting points were determined by using a Thomas–Hoover melting point apparatus and were uncorrected. The 1H and 13C NMR spectra were recorded on a Bruker ACP 300 and Bruker Avance DPX400 spectrometer, and chemical shifts were given in ppm downfield from tetramethylsilane (TMS). IR spectra were taken with a Perkin–Elmer 682

Acknowledgements

We are grateful to the National Science Council, National Chung Cheng University, and Academia Sinica, Republic of China for financial support.

References (57)

  • Y.S. Hon et al.

    Tetrahedron

    (2003)
  • K.C. Nicolaou et al.

    J. Am. Chem. Soc.

    (1992)
    S. Takano et al.

    Chem. Lett.

    (1989)
  • H. Mattes et al.

    J. Org. Chem.

    (1988)
  • Y. Masuyama et al.

    Tetrahedron Lett.

    (1991)
  • R.M. Carlson et al.

    Tetrahedron Lett.

    (1994)
  • T. Martin et al.

    J. Org. Chem.

    (1996)
  • M.M. Murta et al.

    Synth. Commun.

    (1993)
    A.W. Murray et al.

    Chem. Commun.

    (1984)
  • J.P. Burkhardt et al.

    Tetrahedron Lett.

    (1990)
    N.P. Peet et al.

    J. Med. Chem.

    (1990)
    P. Wipf et al.

    Tetrahedron Lett.

    (1992)
    M.R. Angelastro et al.

    J. Org. Chem.

    (1989)
    H.H. Wasserman et al.

    J. Org. Chem.

    (1994)
    H. Sliwa et al.

    J. Org. Chem.

    (1976)
    T. Sakakura et al.

    J. Org. Chem.

    (1987)
    D.G. Melillo et al.

    J. Org. Chem.

    (1987)
    J.S. Nimitz et al.

    J. Org. Chem.

    (1981)
    X. Creary

    J. Org. Chem.

    (1987)
    T. Takahashi et al.

    Synlett

    (1994)
    D. Barton et al.
    (1979)
  • D.C. Craig et al.

    Tetrahedron

    (1997)
  • M. Okabe et al.

    J. Org. Chem.

    (1982)
  • E. Ghera et al.

    J. Org. Chem.

    (1990)
  • Y. Kato et al.

    Tetrahedron Lett.

    (1995)
  • Y.S. Hon et al.

    Chem. Commun.

    (1994)
    Y.S. Hon et al.

    Tetrahedron

    (1998)
  • S. Takano et al.

    Chem. Commun.

    (1988)
    P. Herdewijn et al.

    J. Med. Chem.

    (1986)
  • Y. Nakatsuji et al.

    J. Am. Chem. Soc.

    (1988)
  • A. Hosomi et al.

    Tetrahedron Lett.

    (1980)
  • J.E. Baldwin et al.

    Tetrahedron Lett.

    (1986)
  • J.Y. Zhou et al.

    Synth. Commun.

    (1992)
    S.E. Drewes et al.

    Synth. Commun.

    (1995)
    K. Tanaka et al.

    J. Org. Chem.

    (1986)
    M.B. Isaac et al.

    J. Org. Chem.

    (1997)
  • R.M. Adlington et al.

    J. Chem. Soc., Perkin Trans. 1

    (1994)
  • H. Nishiyama et al.

    Tetrahedron Lett.

    (1982)
    M. Ochiai et al.

    Tetrahedron Lett.

    (1983)
  • R. Ballini et al.

    J. Org. Chem.

    (1999)
    T. Fujiwara et al.

    Bull. Chem. Soc. Jpn

    (1989)
  • P.K. Mandal et al.

    J. Org. Chem.

    (1998)
  • M. Chandrasekharam et al.

    J. Org. Chem.

    (1998)
    K. Narkunan et al.

    Chem. Commun.

    (1998)
    H.S. Lin et al.

    Chem. Commun.

    (1997)
    C.C. Chen et al.

    J. Am. Chem. Soc.

    (1996)
  • C.W. Lee et al.

    Heterocycles

    (1997)
    T. Minami et al.

    J. Chem. Soc., Perkin Trans. 1

    (1990)
  • R.L. Danheiser et al.

    J. Org. Chem.

    (1993)
  • W. Adam et al.

    J. Org. Chem.

    (1991)
  • E. Ghera et al.

    J. Org. Chem.

    (1990)
  • R.M. Carlson et al.

    Synth. Commun.

    (1983)
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