Background

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The Tipson-Cohen reaction was first discovered in Washington D.C. by Stuart Tipson and Alex Cohen.[1] The Tipson-Cohen reaction occurs when two neighboring secondary sulfonyloxy groups in a sugar molecule are treated with zinc dust (Zn) and sodium iodide (NaI) in a refluxing solvent such as N, N-dimethylformamide (DMF) to give an unsaturated carbohydrate.[2] Unsaturated carbohydrates are desired as they are versatile building block that can be used in a variety of reactions.[3] For example, they can be used as intermediates in the synthesis of natural products, or as dienophiles in the Diels-Alder reaction, or as precursors in the synthesis of oligosaccrides.[4]


The Tipson-Cohen reaction goes through a syn or anti elimination mechanism to produce an alkene in high to moderate yields.[5] The reaction depends on the neighboring substituents. A mechanism for glucose and mannose is shown below.[6]


 

Scheme 1: Syn elimination occurs with glucose. Galactose follows a similar syn mechanism.[7] Whereas, anti elimination occurs with mannose.[8] Note that R could be a methane sulfonyl CH2O2S (Ms), or a toluene sulfonyl CH3C5H4O2S (Ts).[9]

Mechanism Study

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Scheme 3: The scheme illustrates the first displacement, the rate determining step and slowest step, where the starting material is converted to the iodo-intermediate.[10] The intermediate is not detectable as it is rapidly converted to the unsaturated sugar.[11] Experiments with azide instead of the iodide confirmed attack occurs at the C-3 as nitrogen-intermediates were isolated.[12] The order of reactivity from most reactive to least reactive is: β-glucose > β-mannose > α-glucose> α-mannose.[13]


The reaction with β –mannose gives low yields and longer reaction times than with β-glucose due to the presence of a neighboring axial substituent (sulfonyloxy) relative to C-3 sulfonyloxy group in the starting material.[14] The axial substituent increases the steric interactions in the transition state, causing unfavorable eclipsing of the two sulfonyloxy groups.[15] α-glucose posses a β-trans-axial substituent relative to C-3 sulfonyloxy (anomeric OCH3 group) in the starting material. The β-trans-axial substituent influences the transition state by also causing an unfavorable steric interaction between the two groups.[16] In the case of α-mannose sugar, both a neighboring axial substituent (2-sulfonyloxy group) and a β-trans-axial substituent (anomeric OCH3 group) are present, therefore significantly increasing the reaction time and decreasing the yield.[17]

Reaction Conditions

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Substratea Time (hours) Yield (%)
β-glucose 0.5 85
β-mannose 2.5 66
α-glucose 12 55
α-mannose 15 10

aSubstrates possess benzylidene protecting groups at C-4 and C-6, OMe groups at anomeric position and OTs groups at C-2 and C-3. Reaction temperature 95-100˚C

Table 1: Reaction times and yield vary on the substrate. β-glucose was found to be the best substrate for the Tipson-Cohen reaction as the reaction time and yield were much superior that any other substrate proposed in the study. [18]

Reaction Scope

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The reaction has been attempted in the microwave, improving yields of α -glucose to 88% and reducing the reaction time significantly to 14 minutes.[19]


The original paper by Tipson and Cohen used acyclic sugars to illustrate the utility of the reaction. Thus the reaction is not limited to cyclic sugars.[20]


Sulphonoxy groups such as Ms and Ts were both used, however it was found that substrates with Ts groups gave higher yields and lower reaction times. [21],[22], [23]

References

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  1. ^ R.S. Tipson and A. Cohen, Carbohydrate Research, 1 (1965), 338-340.
  2. ^ E.Albano, D. Horton, and T. Tsuchiya. Carbohydrate Research, 2 (1966), 349-362
  3. ^ E.Albano, D. Horton, and T. Tsuchiya. Carbohydrate Research, 2 (1966), 349-362.
  4. ^ T. Yamazaki and K. Matsuda. Carbohydrate Research, 50 (1976), 279-281.
  5. ^ T. Yamazaki and K. Matsuda. Journal of the Chemical Society, Perkin Transactions 1, 1 (1977), 1981-1984.
  6. ^ T. Yamazaki and K. Matsuda. Journal of the Chemical Society, Perkin Transactions 1, 1 (1977), 1981-1984.
  7. ^ T. Yamazaki and K. Matsuda. Carbohydrate Research, 50 (1976), 279-281
  8. ^ T. Yamazaki and K. Matsuda. Journal of the Chemical Society, Perkin Transactions 1, 1 (1977), 1981-1984.
  9. ^ T. Yamazaki and K. Matsuda. Journal of the Chemical Society, Perkin Transactions 1, 1 (1977), 1981-1984.
  10. ^ T. Yamazaki and K. Matsuda. Journal of the Chemical Society, Perkin Transactions 1, 1 (1977), 1981-1984.
  11. ^ T. Yamazaki and K. Matsuda. Journal of the Chemical Society, Perkin Transactions 1, 1 (1977), 1981-1984.
  12. ^ T. Yamazaki and K. Matsuda. Journal of the Chemical Society, Perkin Transactions 1, 1 (1977), 1981-1984.
  13. ^ T. Yamazaki and K. Matsuda. Journal of the Chemical Society, Perkin Transactions 1, 1 (1977), 1981-1984.
  14. ^ T. Yamazaki and K. Matsuda. Journal of the Chemical Society, Perkin Transactions 1, 1 (1977), 1981-1984.
  15. ^ T. Yamazaki and K. Matsuda. Journal of the Chemical Society, Perkin Transactions 1, 1 (1977), 1981-1984.
  16. ^ T. Yamazaki and K. Matsuda. Journal of the Chemical Society, Perkin Transactions 1, 1 (1977), 1981-1984.
  17. ^ T. Yamazaki and K. Matsuda. Carbohydrate Research, 50 (1976), 279-281.
  18. ^ T. Yamazaki and K. Matsuda. Carbohydrate Research, 50 (1976), 279-281.
  19. ^ L. Baptistella, A. Neto, et al. Tetrahedron Letters, 34 (1993), 8407-8410.
  20. ^ R.S. Tipson and A. Cohen, Carbohydrate Research, 1 (1965), 338-340.
  21. ^ R.S. Tipson and A. Cohen, Carbohydrate Research, 1 (1965), 338-340.
  22. ^ E.Albano, D. Horton, and T. Tsuchiya. Carbohydrate Research, 2 (1966), 349-362.
  23. ^ T. Yamazaki and K. Matsuda. Carbohydrate Research, 50 (1976), 279-281.