Barton-McCombie Deoxygenation

What Is the Barton-McCombie Deoxygenation Reaction?

The Barton-McCombie deoxygenation reaction is a reaction in which the alcoholic hydroxyl group in the R-OH of an organic compound is replaced by hydrogen to generate the corresponding R-H. Since it was reported by Barton and McCombie in 1975, the reaction has been widely used in organic synthesis and has become a universal method for deoxygenation of alcoholic hydroxyl groups. The traditional Barton-McCombie deoxygenation reaction is to prepare the corresponding thiocarbonyl ester intermediate from alcohol, and then react with organic tin hydride to obtain the final dehydroxylated product.

This reaction has become a cornerstone in organic synthesis, particularly for the selective removal of hydroxyl groups in complex molecules, enabling streamlined access to deoxygenated products with high efficiency. Its utility spans natural product synthesis, medicinal chemistry, and materials science.

• Reagents: Thiocarbonyl derivatives (thionoester or xanthate), tributyltin hydride (Bu₃SnH), radical initiator (e.g., azobisisobutyronitrile (AIBN)).
• Reactants: Alcohols.
• Products: Deoxygenated alkanes.
• Reaction type: Reduction reaction.
• Related reactions: Barton decarboxylation, Hunsdiecker reaction.
• Experimental tips:
  a) Primary alcohols are generally poor substrates due to the instability of primary radicals. Tertiary and secondary alcohols react efficiently.
  b) Avoid substrates prone to radical side reactions (e.g., allylic or benzylic systems).
  c) Tin byproducts (e.g., Bu₃SnS(C=O)R) are removed via aqueous KF treatment, precipitating insoluble tin fluorides.

Fig 1. Barton-McCombie deoxygenation reaction and its mechanism. [1]

Mechanism of Barton-McCombie Deoxygenation

The reaction is a free radical chain reaction, which includes three stages: free radical initiation, transfer, and termination.

• First, the alcohol is converted into the corresponding sulfonate.
• Tributyltin hydride generates tributyltin radicals under the action of azobisisobutyronitrile (AIBN).
• Tributyltin radicals react with sulfonates to generate hydrocarbon radicals.
• The hydrocarbon radicals then capture hydrogen from tributyltin to generate the corresponding hydrocarbon, and at the same time regenerate a tributyltin radical to continue the growth of the free radical chain.

Improvements in the Barton-McCombie Deoxygenation Reaction

The main disadvantage of this reaction is that the tin hydride is expensive, highly toxic, and difficult to remove from the mixture after the reaction. Therefore, the methodological research on this reaction is mainly focused on finding new hydrogen sources. From the current progress, there are four main directions:

a) Use catalytic amounts of tin hydride or its precursors, and use stoichiometric amounts of other hydrogen sources, such as NaBH₄, NaCNBH₃, PMHS (polymethylhydrosiloxane), PhSiH₃;

b) Use modified tin ane, including fluorotin ane;

c) Use immobilized tin ane;

d) Use tin ane substitutes, especially silane.

Application Examples of Barton-McCombie Deoxygenation

• Example 1: The total synthesis of (+)-Antroquinonol, a potential antidiabetic drug, was achieved by Suzuki-Miyaura cross-coupling and Barton-McCombie reaction. Specifically, starting from the readily available mannose diacetonide, a total synthesis of (+)-antroquinonol was achieved in 16 steps with an overall yield of 5.9%. The main features of the synthesis include (i) 6-exo-dig cyclization of the cyclic radical generated by Barton-McCombie deoxygenation to achieve cis-geometry (C₄-OH, C₅-C₇) and (ii) Suzuki-Miyaura coupling for the synthesis of sesquiterpene side chains. [2]
• Example 2: Vavilapalli Satyanarayanade et al. utilized a desymmetrization scheme, Barton-McCombie reaction, Brown asymmetric allylation, and Wacker oxidation in a highly stereoselective synthetic strategy for the C12-C21 common fragment of thermolides. [3]

Fig 2. Synthetic examples via Barton-McCombie deoxygenation reaction.

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References

1. Jie Jack Li. Name Reactions-A Collection of Detailed Mechanisms and Synthetic Applications, Sixth Edition, 2021, 22-24.
2. Sulake, Rohidas S., et al. The Journal of Organic Chemistry, 2015, 80(12), 6044-6051.
3. Satyanarayana, Vavilapalli, et al. Tetrahedron Letters, 2018, 59(29), 2828-2830.