Tipson–Cohen reaction

The Tipson–Cohen reaction is a name reaction first discovered by Stuart Tipson and Alex Cohen at the National Bureau of Standards in Washington D.C.[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]

Background

Unsaturated carbohydrates are desired as they are versatile building blocks that can be used in a variety of reactions.[2] 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 oligosaccharides.[3] The Tipson–Cohen reaction goes through a syn or anti elimination mechanism to produce an alkene in high to moderate yields.[4] The reaction depends on the neighboring substituents. A mechanism for glucopyranosides and mannooyranosides is shown below.[4]

Scheme 1: Syn elimination occurs with the glucopyranosides. Galactopyranosides follows a similar syn mechanism.[3] Whereas, anti elimination occurs with mannopyranosides.[4] Note that R could be a methanesulfonyl CH2O2S (Ms), or a toluenesulfonyl CH3C6H4O2S (Ts).

Reaction mechanism

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.[4] The intermediate is not detectable as it is rapidly converted to the unsaturated sugar. Experiments with azide instead of the iodide confirmed attack occurs at the C-3 as nitrogen-intermediates were isolated. The order of reactivity from most reactive to least reactive is: β-glucopyranosides > β-mannopyranosides > α-glucopyranosides> α-mannopyranosides.

The reaction of β–mannopyranosides gives low yields and required longer reaction times than with β-glucopyranosides due to the presence of a neighboring axial substituent (sulfonyloxy) relative to C-3 sulfonyloxy group in the starting material.[4] The axial substituent increases the steric interactions in the transition state, causing unfavorable eclipsing of the two sulfonyloxy groups. α-Glucopyranosides possess 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. In the case of α-mannopyranosides, 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.[3]

Reaction conditions

Table 1: Reaction times and yield vary on the substrate. The β-glucopyranoside 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.[3]

Substratea Time (hours) Yield (%)
β-glucopyranoside 0.5 85
β-mannopyranoside 2.5 66
α-glucopyranoside 12 55
α-mannopyranoside 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

Reaction scope
  • The reaction has been attempted in the microwave, improving yields with the α-glucopyranoside to 88% and reducing the reaction time significantly to 14 minutes.[5]
  • The original paper by Tipson and Cohen also used acyclic sugars to illustrate the utility of the reaction. Thus the reaction is not limited to cyclic carbohydrate derivatives.[1]
  • Sulphonoxy groups such as methanesulfonyl and toluenesulfonyl were both used, however it was found that substrates with toluenesulfonyl groups gave higher yields and lower reaction times.[1][2][3]

References
  1. R.S. Tipson & A. Cohen (1965). "Action of zinc dust and sodium iodide in N,N-dimethylformamide on contiguous, secondary sulfonyloxy groups: A simple method for introducing nonterminal unsaturation". Carbohydrate Research. 1 (4): 338–340. doi:10.1016/S0008-6215(00)81770-X.
  2. E.Albano, D. Horton & T. Tsuchiya (1966). "Synthesis and reactions of unsaturated sugars". Carbohydrate Research. 2 (5): 349–362. doi:10.1016/S0008-6215(00)80329-8.
  3. T. Yamazaki & K. Matsuda (1976). "Synthesis of methyl 4,6-O-benzylidene-2,3-dideoxy-β-D-erythro-hex-2-enopyranoside by the Tipson-Cohen reaction". Carbohydrate Research. 50 (2): 279–281. doi:10.1016/S0008-6215(00)83860-4.
  4. T. Yamazaki & K. Matsuda (1977). "Steric and electrostatic effects on the elimination of 2- and 3-sulphonyloxy-groups from methyl 4,6-O–benzylidenehexopyranosides". Journal of the Chemical Society, Perkin Transactions 1. 1 (18): 1981–1984. doi:10.1039/p19770001981.
  5. L. Baptistella; A. Neto; et al. (1993). "An improved synthesis of 2,3- and 3,4-unsaturated pyranosides: The use of microwave energy". Tetrahedron Letters. 34 (52): 8407–8410. doi:10.1016/S0040-4039(00)61345-X.
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