Barton-McCombie reaction

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The Barton-McCombie reaction is the deoxygenation of an aliphatic alcohol via thioacylation of the alcohol followed by radical cleavage. Variations of the reaction may employ different thioacyl fragments and hydrogen sources, although S-methyl xanthates and tributylstannane are most commonly used.[1]


Deoxygenation, or the replacement of a hydroxyl group with hydrogen, is a useful simplifying transformation that may also be used to introduce deuterium or tritium in a site-specific manner. In 1975, Barton and McCombie discovered that deoxygenation of aliphatic alcohols could be accomplished through thioacylation of the hydroxyl group followed by treatment with the reducing agent tributylstannane (Eq. 1). They also discovered that the reaction most likely proceeds through a radical chain mechanism involving addition of tributyltin radical to the carbon-sulfur double bond at sulfur, followed by fragmentation and hydrogen abstraction by the resulting carbon-centered radical.[2]


Since Barton and McCombie's seminal discovery, analogous methods have been developed that employ other reducing agents and thioacyl compounds. Because the reaction conditions tolerate a wide range of functional groups and substitution patterns, such deoxygenations have seen considerable use in organic synthesis as either a late-stage, simplifying transformation, or in the modification of complex, natural products.

Mechanism and Stereochemistry

Prevaling Mechanism

The insensitivity of the reduction step to solvent polarity and the need for a radical initiator suggest that the mechanism of this step involves radical intermediates. Initiation produces small amounts of the tributyltin radical, which adds across the carbon-sulfur double bond at sulfur, yielding resonance-stabilized adduct radical II. Irreversible reduction of this intermediate by tributylstannane to form VI via pathway (B) is sometimes a problematic side reaction, depending on the identity of Y and the reaction conditions. Fragmentation of II via pathway (A) affords co-product III and carbon-centered radical IV, which abstracts a hydrogen atom from tributylstannane to yield the product and propagate the radical chain. IV also may add reversibly to starting material I via pathway (C), which in some cases leads to thioester VII (Eq. 2).[1]


In general, the relative rates of pathways (A), (B), and (C) depend on both the nature of the reactants and the reaction conditions (concentration, temperature, etc.). Electronic effects from substituents near the radical center tend to be minimal,[3] although steric compression can significantly affect the ease of fragmentation.[4]


The diastereoselectivity of reductions of tertiary alcohols is generally high in conformationally rigid substrates. Although anomeric effects can favor axial attack in reductions at the anomeric center in pyranoside derivatives,[5] the stereochemical outcome of the majority of free-radical reductions involving HSnBu3 and similarly bulky reagents is dominated by the approach of the hydrogen donor from the less hindered direction, as in the reduction shown in Eq. 3.[6]


Studies of secondary alcohols employing deuterium-based reducing agents have demonstrated that deoxygenations of secondary alcohols can also be highly diastereoselective. For instance, the stereoselectivity of reduction at the 2-position in ribonucleoside derivatives is controlled by the orientation of the pyrimidine base (Eq. 4).[7]


Scope and Limitations

Using the Barton-McCombie reaction, primary, secondary, and tertiary alcohols may be reduced efficiently under appropriate reaction conditions. However, particularly for primary and tertiary alcohols, some substrates have specific concerns. The following sections discuss the scope and limitations of the Barton-McCombie reaction with respect to the thioacylation and reduction steps.

The Thioacylation Step

In a method that has general utility, Vilsmeier-type reagents may be used for thioacylation of primary and secondary alcohols (Eq. 5). The resulting thionoesters efficiently undergo reduction with HSnBu3.[2]


Other O-thioacyl derivatives are obtained by reacting the alcohol with appropriately activated thiocarbonyl compounds. Treating the alcohol with a strong base and carbon disulfide followed by iodomethane is a long-established route to S-methyl xanthates, and a similar reaction of the alkoxide with phenyl isothiocyanate affords thiocarbamates (Eq. 6).[8]


Thioacylation of tertiary alcohols is sometimes complicated by subsequent spontaneous Chugaev elimination,[9] a process that is retarded by the presence of electron-withdrawing substituents (see Eq. 3, above), but is otherwise facile. Some xanthates may be prepared and subsequently reduced at room temperature (Eq. 7) but others are even less stable, and alternative substrates must be prepared.


For those cases, the tertiary alcohol may be deoxygenated via the corresponding O-thioformate. Although the parent Vilsmeier reagent cannot be used for this transformation because side products derived from carbocation formation predominate, an effective method employs copper-catalyzed imidate formation followed by exchange with hydrogen sulfide (Eq. 8).[10]


The Reduction Step

Tributylstannane is the most common hydrogen donor employed for the Barton-McCombie reaction. However, this reagent is not without disadvantages, including the formation of stoichiometric amounts of tin-containing co-products and a propensity to react with reducible functional groups, notably C-Br and C-I bonds. In addition, some organotin compounds are significantly toxic towards both mammals and microorganisms. For secondary alcohols, the efficiency of tributylstannane reductions is largely independent of the nature of the thioacyl fragment (Eq. 9).[11][12][13][14][15]


Tributylstannane will also deoxygenate suitably derivatized primary alcohols, although higher temperatures are required for optimal yields, reflecting the lower rate of fragmentation.[16] An important limitation of the scope of the reduction step, common to all reducing agents, is related to the possibility of transformations of the carbon-centered radical. Fragmentation to form an alkene takes place when the carbon β- to the radical center bears a chloro, isocyano, nitro, thio or sulfonyl group. With the exception of sterically crowded alkoxy groups,[17] alkoxy, aryloxy and acyloxy groups do not eliminate. However, thioacyl groups will do so, and this forms the basis of a free-radical method for converting diols into olefins (Eq. 10).[18]


The use of catalytic amounts of tin avoids the production of stoichiometric amounts of potentially toxic by-products. Silanes such as PMHS (polymethylhydroxysilane, HO(MeSi(H)O)nH, n ~ 35) may be used as terminal hydrogen sources in these reactions (Eq. 11).[19]


Reductions of O-thioesters that do not involve tin-based reagents have also been devised. Simple trialkylsilanes may be used, although the lower H-donating efficiency requires either the use of catalytic amounts of a hindered thiol plus an initiator,[20] or larger amounts of an initiator alone. Tris(trimethylsilysilane) is a comparable donor to tributylstannane, and can be used as a direct replacement.[21] Compounds with P–H bonds, notably diakyl phosphites[22] and hypophosphorous acid[23] are inexpensive, low toxicity donors that again require larger amounts of the initiator. Recent variations include the use of formate ion as the H-donor, with stoichiometric persulfate as the radical source,[24] and the combination of a trialkylborane with water and oxygen, in which complexed water is the H–donor.[25]

Synthetic Applications

Because the Barton-McCombie reaction employs mild conditions and has high functional group tolerance, it is useful for the late-stage modification of natural products or synthetic intermediates. For instance, synthetic efforts toward spinosyn A involved deoxygenation of a late synthetic intermediate. Among other functional groups, a vinyl bromide and alkene in the substrate were not affected by the reaction conditions (Eq. 12).[26]


The reaction has also been used for the synthesis of unique molecular architectures, which may involve the use of carbonyl or hydroxyl groups as functional handles which can be removed via deoxygenation. A synthesis of azafenestrane nicely illustrates this idea (Eq. 13).[27]


Comparison to Other Methods

Alternative methods for deoxygenation may involve either radical or ionic intermediates. Among radical-based methods, deacylation to afford the alcohol starting material is a common problem when other activating groups, such as oxalates, are employed.[28] Photochemical methods may suffer from the same problem, and successful photochemical deoxygenations are generally less efficient than those that employ radical initiators (Eq. 14).[29]


Dissolving metal or electrochemical conditions can be used to effect deoxygenation via carbanionic intermediates; however, the substrate scope of these methods is severely limited because the reaction conditions are strongly reducing. In addition, deacylation can be a problem under these conditions. Phosphorodiamidates do not undergo competitive deacylation (Eq. 15).[30]


Reductions of electrophilic, unhindered sulfonates with metal hydrides represent another method for ionic deoxygenation (Eq. 16).[31]


Experimental Conditions and Procedure

Typical Conditions

The reaction is typically carried out under an inert atmosphere of argon or nitrogen. The efficiency of the reaction does not depend on solvent, and a wide variety of solvents can be employed, including aromatic hydrocarbons, dioxane, alkanes, acetone, ethyl acetate, acetonitrile and dichloromethane. The most common radical initiators used are AIBN, peroxides, and trialkylborane-air, and initiators are essential when hydrogen donors weaker than tributyltin hydride are used. Workup can be complex because the tributyltin sulfide by-products of the reaction can be difficult to separate. Several procedures have been devised to address this problem; however, the appropriate workup method for a given reaction depends on the polarity of the deoxygenated product.[32][33]

Example Procedure[2]


5α-Cholestan-3β-ol (2.50 g; 6.44 mmol) and 1,1'-thiocarbonyldiimidazole (2.00 g, 11.22 mmol) were heated under reflux for 3 h in 1,2-dichloroethane (25 mL). The solvent was evaporated, the residue was dissolved in CH2Cl2, and the solution was washed with 5% w/v tartaric acid, H2O, and saturated NaHCO3, dried over MgSO4, and evaporated. The residue was recrystallized from Et2O/MeOH, by evaporating the Et2O at rt on a rotary evaporator, to give 1-(5α-cholestan-3β-yloxythiocarbonyl) imidazole (2.92 g, 90%): mp 151–152°; [α]D22 –57.2 (c 0.8, CHCl3); IR (Nujol) 1410, 1305, 1265, 1125, 1010 cm–1; 1H NMR (CDCl3) δ 8.33 (s, 1H), 7.62 (s, 1H), 7.02 (s, 1H), 5.42 (m, 1H). Anal. Calcd for C31H50N2OS: C 74.65; H, 10.1; N, 5.6; S, 6.4. Found: C, 74.6; H, 9.9; N, 5.65; S, 6.4. A solution of the foregoing compound (0.51 g, 1.022 mmol) in toluene (25 mL) was added over 0.5 h to a refluxing solution of Bu3SnH (0.45 g, 1.55 mmol) in toluene (20 mL) under argon. The solution was refluxed until TLC indicated complete consumption of the starting material (1.5 h). The solution was evaporated and the residue chromatographed on alumina (Brockmann grade III), eluting with pentane. Evaporation of the product-containing fractions and recrystallization from acetone/methanol gave 5α-cholestane (0.30 g, 79%). Mp and mixed mp with an authentic sample 78.5–79.5 °C.


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