金属氢化物如氢化铝锂、硼烷、硼氢化钠（钾）是实验室中常用的将羧酸还原成相应的伯醇的还原剂。氢化铝锂是还原羧酸的最常用试剂。硼烷是选择性的还原羧酸为醇的优良试剂，条件温和，反应速度快，且不影响分子中存在的硝基、卤素等基团。

1、氢化铝锂还原羧酸为醇

氢化铝锂还原羧酸，反应可在十分温和的条件下进行，一般不会停止在醛的阶段。即使位阻较大的酸，也有较好的收率，所以得到广泛的应用。此类反应放出氢气，因此反应要做通风良好的通风橱里进行。

Organic Syntheses, Coll. Vol. 7, p.530; Vol. 63, p.136.

An oven-dried, 3-L, three-necked flask equipped with a mechanical stirrer, a Friedrich condenser, and a nitrogen-inlet tube is flushed with nitrogen, and then charged with a suspension of lithium aluminum hydride (47.9 g, 1.26 mol) in 1200 mL of tetrahydrofuran (THF). The mixture is cooled (10°C, ice bath) and L-valine (100 g, 0.85 mol) is added in portions over a 30-min period from a 200-mL round-bottomed flask connected to the reaction flask via a flexible plastic sleeve so as not to produce too vigorous an evolution of hydrogen. After the addition is complete, the plastic sleeve is replaced by a stopper, the ice bath is removed, and the reaction mixture is warmed to room temperature and then refluxed for 16 hr. The reaction mixture is then cooled again (10°C, ice bath) and diluted with ethyl ether (1000mL). The reaction is quenched over a 30-min period with water (47 mL) (Caution!, aqueous15% sodium hydroxide (47 mL, over 20 min), and water (141 mL, over 30 min). The solution is stirred for 30 min and the white precipitate is filtered. The filter cake is washed with ethyl ether (3 × 150 mL) and the organic filtrates are combined, dried with anhydrous sodium sulfate, and concentrated under reduced pressure. Distillation of the residue under vacuum affords L-valinol (63.9–65.7 g, 73–75%) as a clear liquid: bp 63–65°C (0.9 mm): [α]D20 +14.6° (neat); nD20 1.455; IR (neat) cm1: 3300, 1590; 1H NMR (CDCl3) δ: 0.92 (d, 6 H), 2.38–2.74 (m, 4 H), 3.13–3.78 (m, 2 H).

2、 硼烷还原羧酸为醇

硼烷为亲电性还原剂，首先是由缺电子的硼原子和羰基氧原子上未共用电子相结合，然后硼原子的氢，以负氢离子形式转移到羰基碳原子上而使之还原成醇。

在羧酸的还原过程中，可能是先生成三酰氧基硼烷，然后酰氧基中氧原子上未共用的电子与缺电子的硼原子之间可能发生相互作用。生成中间体而使酰氧基硼烷中的羰基较为活波，进一步按羰基还原的方式得到相应的伯醇。

硼烷还原羧基的速度比还原其他基团快，因此，当羧酸衍生物分子中有氰基、酯基时，若控制硼烷的用量并在低温反应，可选择性地还原羧基为相应的醇，而不影响其他取代基。硼烷还原羧酸的速度，脂肪酸大于芳香酸，位阻小的羧酸大于位阻大的羧酸，但羧酸盐则不能还原。对脂肪酸酯的还原速度一般较羧酸慢，对芳香酸酯几乎不发生反应，这是由于芳环和羰基的共轭效应，降低了羰基氧上的电子云密度，使硼烷的亲电进攻难于进行。

2.1 硼烷还原羧酸

Organic Syntheses, Coll. Vol. 7, p.530; Vol. 63, p.136.

A 2-L, three-necked, round-bottomed flask is equipped with a mechanical stirrer, heating mantel, 250-mL graduated addition funnel, and an 8-in., air-cooled reflux condenser (West type) topped with a water-cooled distillation head and a 1-L receiving flask. It is connected to a nitrogen line through the still head. The glassware is either oven-dried and cooled in a desiccator or flame-dried and assembled while still hot. The assembly is flushed with nitrogen and charged with 200 g of L-valine (1.7 mol), 400 mL of tetrahydrofuran (THF), and 210 mL of freshly distilled boron trifluoride etherate (242 g, 1.7 mol). The mixture is heated at a rate sufficient to cause the THF to reflux gently and 188 mL (1.88 mol) of borane–methyl sulfide complex (BMS) is added dropwise over the course of 2 hr. The solution is then refluxed for 18 hr. The methyl sulfide that has collected at the stillhead is discarded, and the reaction mixture is cooled to 0°C and quenched by the slow addition of 200 mL of methanol. The addition funnel is replaced by a glass stopper, and the air-cooled condenser is removed, leaving the flask equipped for distillation of solvent through the distillation head. The reaction

mixture is concentrated under reduced pressure with heating and stirring. The distillation head is replaced by a water-cooled reflux condenser, and the residue is dissolved in 1 L of 6 M sodium hydroxide and refluxed for 4 hr. The mixture is saturated with potassium carbonate (ca. 400 g); cooled; filtered through a Celite pad on a coarse, fritted funnel; and extracted with three 1-L portions of chloroform. The combined extracts are washed with three portions of saturated sodium chloride (500 mL each), stirred over anhydrous potassium carbonate for 24hr, and concentrated under reduced pressure to give a yellow oil. The crude material is vacuum distilled to give 77.5 g (44%) of purified L-valinol, bp 62–67°C/2.5 mm(Note 6); [α]D20 + 14.6° (neat), nD20 1.455; IR (neat film) cm−1: 3300 (OH), and 1590 (NH2); NMR δ: 0.92 (d, 6 H), 1.54 (m, 1 H), 2.38–2.74 (m, 4 H), 3.13–3.78 (m, 2 H).

2.2 硼烷还原α,β-不饱和acid 到α,β-不饱和醇

Organic Syntheses, Coll. Vol. 7, p.221 (1990); Vol. 64, p.104 (1986).

A dry, 2-L, one-necked, round-bottomed flask is equipped with a 1-L pressure-equalizing funnel and a large magnetic stirring bar. The system is flame-dried under an internal atmosphere of dry nitrogen. The flask is charged with 300 mL of anhydrous tetrahydrofuran and 100 g of monoethyl fumarate. The solution is then stirred under nitrogen and brought to about −5°C using an ice–salt/methanol bath (−10°C). A 1 M solution of 700 mL (0.70 mol) of borane–tetrahydrofuran complex is cautiously added dropwise (rapid H2 evolution occurs) with rigorous temperature control to avoid an exothermic reaction. The ice–salt bath is

maintained in position throughout the 90 min of addition. The stirred reaction mixture is then gradually allowed to warm to room temperature over the next 8–10 hr. The reaction is carefully quenched at room temperature by dropwise addition of 1 : 1 water : acetic acid (ca.20 mL) with stirring until no more gas evolution occurs. The reaction is concentrated at room temperature and water pump pressure to a slurry by removal of most of the tetrahydrofuran.

The slurry is carefully poured over a 20-min period into 300 mL of ice-cold, saturated sodium bicarbonate solution with mechanical stirring to avoid precipitation of solids, and the product is extracted with 300 mL of ethyl acetate. The aqueous layer is again extracted with 100 mL of ethyl acetate. The organic layers are combined, washed once with 200 mL of saturated sodium bicarbonate, then dried well with anhydrous magnesium sulfate.

Solvent removal at reduced pressure gives 61 g (67% yield) of essentially pure ethyl hydroxycrotonate.An analytical sample may be prepared by quick distillation (or Kugelrohr distillation) at 117–120°C (15 mm), but there is significant loss of material because of decomposition in the distillation pot. From 1 g of product, 0.72 g of pure material is obtained in this way, and recovery decreases as scale of distillation increases.

3 、Lewis 酸存在下硼氢化钠还原羧酸为醇

硼氢化钠通常不能用来直接还原羧酸，但是Lewis 酸的存在可大大提高其还原能力，从而用于羧酸的还原。由于LAH 和硼烷的价格相对要贵，因此工业上大量生产时，一般都应用该方法，比较常用的体系为： NaBH4-BF3, NaBH4-ZnCl2.

J. Org. Chem., Vol. 63, No. 12, 1998.

To a THF (220 mL) solution of 2-(carboxymethyl)-4-nitrobenzoic acid, 7a (10.0 g, 44.4 mmol), was added sodium borohydride (5.06 g, 133 mmol) in portions. The contents were cooled to 0 °C, and boron trifluoride diethyl etherate (21.3 mL, 133 mmol) was added dropwise over 1 h. The contents were allowed to warm to 25 °C and stirred for 16 h. The reaction was cooled to 0 °C and cautiously quenched with aqueous sodium hydroxide (1 N,178 mL). The contents were stirred for 3 h, THF was removed under vacuum, the resulting aqueous suspension was cooled to 0 °C, and the product was filtered off. After drying, the product was obtained as a white solid: 7.78 g (89%)

4、 硼氢化钠还原活性酯或酰氟为醇

另外有时对于比较复杂的分子，常常将酸做成活性酯后再用NaBH4直接还原，常用的方法为与氯甲酸乙酯或氯甲酸乙酯反应生成活泼的混酐，或与CDI得到活泼酰基眯唑。 最近有报道用三氟均三嗪生成酰氟后用NaBH4还原得到醇。

4.1 、酸转化为活性酯还原示例

Patent; BAYER PHARMACEUTICALS CORPORATION; Publ.: WO2005/35507 A2 (2005/04/21), Appl.: WO2004-US33430 (2004/10/08).

To a cloudy solution of 4- {4- [ (2-amino-6-phenylpyrimidin-4-yl) amino] phenoxy}

pyridine-2-carboxylic acid (748 mg, 1.87 mmol, Example 20) in anhydrous DMF (50 mL) at rt was added carbonyldiimidazole (456 mg, 2.81 mmol). The white suspension was stirred at 80'C overnight, concentrated to a volume of 10 mL, and diluted with anhydrous THF (7 mL). The reaction mixture was cooled to 0 .deg.C and water (10 mL) was added. The mixture was vigorously stirred as NaBH4 (142 mg, 3.75 mmol) was added and was allowed to warm from

0 .deg.C to rt over 2 h before it was quenched with conc. HC1 (1 mL) in an ice bath. After stirring for 15 min, the mixture was slowly added to a stirred solution of sat. NaHC03 (20 mL) at 0 .deg.C. After stirring for 30 min, it was extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over Na2S04, filtered, and concentrated to give an off-white gum (420 mg, 85percent pure). The crude material (100 mg) was purified by prep HPLC purification to give 37 mg (40percent yield) of the title compound as a colorless gum. lEI NMR (DMSO-d6) 8 10.8 (s, 1H), 8.55 (d, 1H), 7.90 (m, 2H), 7.75 (m, 2H), 7.60 (m, 3H), 7.35 (d, 2H), 7.20 (m, 2H), 6.60 (s, 1H), 4.60 (s, 2H); MS ES 386 (M+H) + calcd 386, RT = 1.73 min.

4.2 、酸化为酰氟还原示例

J. Org. Chem. 1996, 61, 6994-6996.

Pyridine (80 μL,1 mmol) and subsequently cyanuric fluoride(180 μL, 2 mmol) were added to a stirred solution of the acid or N-protected amino acid or dipeptide (1 mmol) in CH2Cl2 (2.5 mL), kept under a N2 atmosphere, at -20 to -10 °C. Precipitation of cyanuric acid occurred and increased gradually as the reaction proceeded. After the mixture was stirred at –20 to -10 °C for 1 h, ice-cold water was added along with 15 mL of additional CH2Cl2. The organic layer was separated, and the aqueous layer was extracted once with CH2Cl2 (5 mL).

The combined organic layers were washed with ice-cold water (10 mL), dried (Na2SO4), and concentrated under reduced pressure to a small volume (2 mL). NaBH4 (76 mg, 2 mmol) was added in one portion, and MeOH (2 mL) was then added dropwise over a period of 10-15 min at rt. The reaction mixture was neutralized with 1 N H2SO4, and the organic solvents were evaporated under reduced pressure. The residue was treated with EtOAc (10 mL) and H2O (5

mL); the organic layer was separated, and the aqueous layer was extracted with EtOAc (2 × 8mL). The combined organic layers were washed consecutively with 1 N H2SO4 (5 mL) and H2O (2×10 mL) and dried (Na2SO4), and the solvent was evaporated under reduced pressure. The residue was purified by distillation or column chromatography using EtOAc/petroleum ether (bp 40- 60 °C) (1:1) as eluent.

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