金屬氫化物如氫化鋁鋰、硼烷、硼氫化鈉（鉀）是實驗室中常用的將羧酸還原成相應(yīng)的伯醇的還原劑。氫化鋁鋰是還原羧酸的最常用試劑。硼烷是選擇性的還原羧酸為醇的優(yōu)良試劑，條件溫和，反應(yīng)速度快，且不影響分子中存在的硝基、鹵素等基團。
1、氫化鋁鋰還原羧酸為醇
氫化鋁鋰還原羧酸，反應(yīng)可在十分溫和的條件下進行，一般不會停止在醛的階段。即使位阻較大的酸，也有較好的收率，所以得到廣泛的應(yīng)用。此類反應(yīng)放出氫氣，因此反應(yīng)要做通風(fēng)良好的通風(fēng)櫥里進行。
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、 硼烷還原羧酸為醇
硼烷為親電性還原劑，首先是由缺電子的硼原子和羰基氧原子上未共用電子相結(jié)合，然后硼原子的氫，以負氫離子形式轉(zhuǎn)移到羰基碳原子上而使之還原成醇。
在羧酸的還原過程中，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電子與缺電子的硼原子之間可能發(fā)生相互作用。生成中間體而使酰氧基硼烷中的羰基較為活波，進一步按羰基還原的方式得到相應(yīng)的伯醇。
硼烷還原羧基的速度比還原其他基團快，因此，當羧酸衍生物分子中有氰基、酯基時，若控制硼烷的用量并在低溫反應(yīng)，可選擇性地還原羧基為相應(yīng)的醇，而不影響其他取代基。硼烷還原羧酸的速度，脂肪酸大于芳香酸，位阻小的羧酸大于位阻大的羧酸，但羧酸鹽則不能還原。對脂肪酸酯的還原速度一般較羧酸慢，對芳香酸酯幾乎不發(fā)生反應(yīng)，這是由于芳環(huán)和羰基的共軛效應(yīng)，降低了羰基氧上的電子云密度，使硼烷的親電進攻難于進行。
2.1 硼烷還原羧酸
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 硼烷還原α,β-不飽和acid 到α,β-不飽和醇
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 酸存在下硼氫化鈉還原羧酸為醇
硼氫化鈉通常不能用來直接還原羧酸，但是Lewis 酸的存在可大大提高其還原能力，從而用于羧酸的還原。由于LAH 和硼烷的價格相對要貴，因此工業(yè)上大量生產(chǎn)時，一般都應(yīng)用該方法，比較常用的體系為： 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、 硼氫化鈉還原活性酯或酰氟為醇
另外有時對于比較復(fù)雜的分子，常常將酸做成活性酯后再用NaBH4直接還原，常用的方法為與氯甲酸乙酯或氯甲酸乙酯反應(yīng)生成活潑的混酐，或與CDI得到活潑?；[唑。 最近有報道用三氟均三嗪生成酰氟后用NaBH4還原得到醇。
4.1 、酸轉(zhuǎn)化為活性酯還原示例
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 、酸化為酰氟還原示例
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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