Reduction of carboxylic esters to alcohols by lithium borohydride

Reduction of carboxylic esters to alcohols by lithium borohydride
Generally speaking, the reducing ability and substrate adaptation range of lithium borohydride and sodium borohydride are about the same. However, we encountered a substrate in the experiment, the use of sodium borohydride reduction of chlorine atoms quickly hydrolyzed, even in anhydrous solvent chlorine atoms are quickly off; using LiAlH4 reduction at low temperatures, the reaction is very heterogeneous. Later, we tried to use lithium borohydride for reduction, and achieved better results. However, the reaction time can not be too long, not waiting for the raw materials to react to the end of the quenching process, otherwise the chlorine atom will also be gradually hydrolyzed.
Reduction of carboxylic acid

Carboxylic acid is much less active than carboxylic acid ester. Commonly used reduction methods are lithium aluminum hydride, borane, sodium borohydride, potassium borohydride and so on.
Reduction of carboxylic acids to alcohols by lithium aluminum hydride
Lithium aluminum hydride can reduce carboxylic acids to alcohols in high yields for most substrates and is the most common method for reducing carboxylic acids. However, lithium aluminium hydride as a reducing agent has poor selectivity, often the carboxyl group and other functional groups are reduced; on the other hand, lithium aluminium hydride is expensive, the anhydrous treatment of the reagent is very strict, so that its practical application, especially in the industrial application of the limitations. Due to the low activity of carboxyl group, the reduction of carboxyl group by LiAlH4 below -20 degrees Celsius is very slow or even non-reactive, so the method of lowering the reaction temperature is not generally used to avoid the reduction of other groups.

Reduction of carboxylic acid to alcohol by borane
Borane is a strong reducing agent, which can reduce most carboxylic acids to alcohols at room temperature with good selectivity. Controlling the amount of borane and reacting at low temperatures avoids reducing the cyano and ester groups in the molecule. Borane reduces fatty acids and most aromatic acids very well, but reacts slowly or not at all with some aromatic acids.
In addition, borane is also very easy to reduce aldehydes, ketones, epoxides and lactones, etc., but the reaction of reducing esters is slow, and almost no reaction occurs for aromatic esters, and under the same conditions, it can’t reduce chlorides, nitro compounds and sulfones.
NaBH4/I2 system to reduce carboxylic acid esters into alcohols
Sodium borohydride can only reduce aldehydes, ketones, acyl halides and lactones, and it is difficult to reduce carboxylic acids. However, its reduction system with iodine is an excellent reagent for the reduction of carboxylic acids.Bhaskar et al. investigated the reduction of common mono acids, α,β-unsaturated acids, carboxylic esters, and dicarboxylic acids with the NaBH4/I2 system. The experimental operation was carried out by adding sodium borohydride to the carboxylic acids and then adding iodine after the system gave off hydrogen. The results showed that the above monoacids were reduced in high yields of 92%-98%; the α- and β-unsaturated acids were reduced to the corresponding α- and β-unsaturated alcohols, and the double bonds were not reduced; only the carboxyl group was reduced when the carboxyl group and the ester group coexisted, even if the substituents of the two groups were very close to each other.
Reduction of carboxylic acid esters to alcohols by Zn(BH4)2
Most metal borides cannot reduce carboxylic acids directly, and other reagents, such as AlCl3 and I2, need to be added to improve their reducibility. However, Zn(BH4)2, as a mild reducing agent, can easily reduce fatty acids and aromatic acids to alcohols. The whole reaction can be completed with only stoichiometric amount of zinc borohydride, and the yield of alcohol is 80 % to 95 %. The reaction formula is as follows.

Carboxylic acid reacts with zinc borohydride to first produce an acyloxyborohydride intermediate, and zinc borohydride can reduce this intermediate to an alcohol, so it can reduce carboxylic acid to alcohol smoothly. When there are functional groups such as bromine, chlorine and nitro in the carboxylic acid molecule, these groups do not react, but the carbon-carbon double bond is subject to borohydride reaction.
Reduction of carboxylic acid esters to alcohols in the NaBH4/BOP system
Carboxylic groups are more difficult to reduce, so another way to reduce carboxylic acids to alcohols is to convert the carboxylic acids to other active derivatives before reducing them with sodium borohydride.In 1998, McGeary reported a one-step reduction of a carboxylic acid to an alcohol using BOP, DIPEA, and sodium borohydride.1,2 The reduction of carboxylic acids to alcohols in a NaBH4/BOP system is a simple process that can be accomplished in a single step. A study of a series of carboxylic acid reduction reactions revealed that the system is highly reductive, reducing fatty acids, aromatic acids, and high site-resistant acids (e.g., adamantylcarboxylic acid) in high yields. Groups such as -NO2, -CN, -COOR, -X, and -N3 are very stable to this reagent. However, the reduction of cinnamic acid indicates that the double bond conjugated to the carboxyl group will be partially reduced. A possible mechanism for this reaction is that the carboxylic acid first reacts with the BOP reagent and DIPEA to form a reactive carboxylic acid ester, which reacts rapidly with NaBH4 to form the corresponding alcohol.
DCC/LiBH4 system
The mechanism of carboxylic acid reduction in the DCC/LiBH4 system is similar to that of the NaBH4/BOP system, in that DCC first reacts with the carboxylic acid to produce a reactive intermediate, which is rapidly reduced to an alcohol by LiBH4.
It is shown that the reaction is rapid