醛和酮转变成醇

学术 2025-01-14 08:30 上海

醛和酮还原转变成醇的方法一直是分别制备伯醇和仲醇的一个较为常用的方法。还原醛和酮到醇主要方法可以分为两类：化学还原法和催化氢化法。

一、和酮的加氢还原

醛和酮的羰基也可通过加氢还原为相应的伯醇和仲醇。催化剂一般为负载在载体上的镍、铬、铜或铜铬等。若加氢原料含有硫化物，则采用镍、钴或钨的氧化物或硫化物型抗硫催化剂。

醛和酮的氢化活性通常大于芳环而小于不饱和键。醛比酮更易氢化，所以醛加氢条件比较温和，一般温度为50～150℃（采用镍或铬催化剂）或200～250℃（采用硫化物催化剂）；而酮加氢的条件在采用上述相同的催化剂时则相应地温度为150～250℃及300～350℃。为了加速反应，及提高平衡反应的转移，这类化合物加氢时也在压力下进行。用镍催化剂时，压力为1～2Mpa，铬催化剂时为5～20Mpa，而用硫化物催化剂时则为30Mpa。

脂肪族醛，酮的氢化活性较之芳香族醛，酮为低，通常用Raney镍和铂为催化剂，而钯催化剂的效果较差。一般需在较高温度和压力下还原。例如，由葡萄糖氢化得山梨醇（sorbitol）。

芳香醛酮的氢化还原，如用钯为催化剂，在加氢剧烈时生成的醇会进一步氢解为烃特别对于芳环上有强推电子基团存在或二芳基酮（参见脱羰基一文）。但如选用适当活性的Raney镍为催化剂，在温和的条件下，可得到醇。如天麻素（gastrodine）中间体的制备。

催化剂钌，铑，铱等金属的三苯膦等配合物，在强碱条件下，可成功地还原脂肪酮和芳香酮为相应的醇¹。

1.1

醛和酮的加氢还原示例1

In a 2-l. three-necked flask equipped with a stirrer and thermometer are placed 336 g. (2.62 moles) of 3,4-dihydro-2-methoxy-4-methyl-2H-pyran, 630 ml. of water, and 24 ml. of concentrated hydrochloric acid. The mixture is stirred for 2 hours, during which the temperature may reach 50℃ but should not be permitted to rise higher. Solid sodium bicarbonate is then added until the solution is neutral to pH indicator paper. The entire reaction mixture weighing about 1 kg. together with 39 g. of Raney nickel2 is introduced into a 3-l. stainless-steel rocking hydrogenation autoclave. A hydrogen pressure of at least 1625 p.s.i. is applied, and the autoclave is heated to 125℃ and held there with shaking for 4 hours. The mixture is allowed to cool overnight, and the catalyst is separated either by suction filtration through Filter-Cel or by centrifugation. The solution is distilled through a 12-in. Vigreux column. After the methanol and water are separated, the 3-methyl-1,5-pentanediol distils at 139–146℃/17 mm., 149–150℃/25 mm. The yield is 251–256 g. (81–83%), n25D 1.4512–1.4521.

二、金属还原

醛、酮能被多种金属还原剂还原成醇。这些金属有锂、钠、钾碱金属; 铝、铁、锌等。他们和特定的试剂配合成常用的还原体系。如锂、钠、钾－氨、钠、钾－醇、铝－汞、铁-乙酸、锌-乙醇等。如钙拮抗剂盐酸马尼地平(Manidipine)中间体二苯甲醇的的制备，通过锌-乙醇还原二苯甲酮的收率达到90％～92％。

2.1

Na-NH3体系还原酮示例2

A 5-L, three-necked, round-bottomed flask is equipped with a variable speed Hershberg stirrer and a 500-mL Dewar condenser filled with dry ice–acetone and connected by its upper joint to a mineral oil bubbler through which passes dry nitrogen gas. The flask is immersed in a dry ice–acetone bath, flushed well with nitrogen and 3000 mL of ammonia is condensed into the flask via a glass tube passed through a rubber septum in the remaining neck of the flask. Clean sodium, 125 g (5.43 g-atom), is added slowly to the ammonia with slow stirring. Then 250.3 g (0.906 mol) of 5-methyl-2-[1-methyl-1-(phenylmethylthio)ethyl]cyclohexanone and 72.5 mL (1.8 mol) of methanol in 625 mL of anhydrous ether are added dropwise via a pressure-equalized addition funnel over 5 hr to the vigorously stirred (ca. 500 rpm) solution. Stirring is continued an additional 30 min following which 150 mL of methanol is added over 2.5 hr dropwise (to avoid a violent eruption). The solution is allowed to warm slowly and the addition funnel and the condenser are removed to allow the ammonia to evaporate overnight. The reaction flask is immersed in an ice bath and 700 mL of water is added cautiously over an hour to the yellow solid left by evaporation of the ammonia. The solution is transferred to a 2-L separatory funnel and extracted with two 200-mL portions of ether, which are discarded. The aqueous layer is poured into a mixture of 500 mL of concentrated hydrochloric acid and 1000 g of ice, transferred to a 4-L separatory funnel, and extracted with four 200-mL portions of ether. The combined ether extracts are washed with 200 mL of water and 200 mL of saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated by rotary evaporation at aspirator vacuum. The residual liquid is placed under reduced pressure (0.2 mm) for 1 hr to remove the remaining solvent to give 137–140 g (80–82%) of an orange oil that is a diastereomeric mixture of which the major component constitutes 80%, as indicated by 13C NMR.

2.2

Na-EtOH体系还原酮示例3

In a 3-l. round-bottomed flask, fitted with an efficient Liebig condenser (100 by 1 cm.), 228 g. (2 moles) of methyl n-amyl ketone is dissolved in a mixture of 600 cc. of 95 per cent alcohol and 200 cc. of water. One hundred thirty grams (5.6 gram atoms) of sodium in the form of wire is gradually added through the condenser. During the addition of the sodium the flask is cooled with running water so that the reaction does not become unduly violent.

When the sodium has dissolved, 2 l. of water is added and the mixture is cooled to 15℃. The upper oily layer is then separated, washed with 50 cc. of 1:1 hydrochloric acid and then with 50 cc. of water, dried over 20 g. of anhydrous sodium sulfate, and distilled with a fractionating column. After a small fore-run of low-boiling liquid, the pure heptanol distils at 155–157.5℃. The yield is 145–150 g. (62–65 per cent of the theoretical amount).

2.3

Na （Hg）体系还原酮示例4

An amalgam prepared from 9.0 g. (0.39 atom) of sodium and 750 g. (55 cc.) of mercury is warmed to about 50℃in a 500-cc. Pyrex round-bottomed flask. To it is then added a cold suspension of 25 g. (0.13 mole) of xanthone in 175 cc. of 95 per cent ethyl alcohol. The flask is at once stoppered, held in a cloth, and vigorously shaken, the stopper being raised from time to time to release any pressure. The temperature rises rapidly to 60–70℃. The solid xanthone rapidly goes into solution, a very faint and transient blue color being developed. At the end of about five minutes the alcoholic solution is clear and practically colorless.

After a further ten-minute shaking the mercury is separated and washed with 10–15 cc. of alcohol. The alcoholic solution is filtered while warm and slowly poured with stirring into 2 l. of cold distilled water. The precipitated xanthydrol is filtered with suction, washed with water until free of alkali, and dried at 40–50℃ to constant weight. The crystalline product, which weighs 23–24 g. (91–95 per cent of the theoretical amount), melts at 121–123℃.

2.4

Fe-HOAc体系还原酮示例5

In a 12-l. flask fitted with a mechanical stirrer and a short reflux condenser are placed 1800 g. (32.2 atoms) of iron filings, 3 l. (52.5 moles) of glacial acetic acid, 3 l. of water, and 450 g. (3.95 moles) of heptaldehyde. The mixture is heated on the steam bath, with stirring, for six to seven hours. The flask is then fitted to an apparatus for steam distillation and the mixture distilled in a current of steam until no more oil passes over (7–8 l. of distillate). The oil is then separated, and the aqueous part distilled to recover a small quantity of dissolved or suspended heptyl alcohol.

The combined product is mixed with 1 l. of 20 per cent sodium hydroxide solution and stirred on the steam bath for four hours, in order to hydrolyze a small proportion of heptyl acetate. The oil is then separated and distilled, and the portion boiling at 172–176℃ is collected. The residue in the flask is mixed with about 100 cc. of water and distilled, whereupon a further small quantity of oil passes over with the steam. This distillate and the forerun are freed of the bulk of the water in a separatory funnel and distilled from a smaller flask. In this way the total yield of n-heptyl alcohol boiling at 172–176℃ (uncorr.) is 350–370 g. (75–81 per cent of the theoretical amount). The alcohol may be redistilled under reduced pressure, when it passes over almost without loss at 71–72℃/12 mm.

2.5

Zn-EtOH体系还原酮示例6

In a 3-l. round-bottomed flask fitted with a mechanical stirrer are placed 200 g. of technical flake sodium hydroxide, 200 g. of benzophenone, 2 l. of 95 per cent alcohol, and 200 g. of technical zinc dust. The stirrer is started and the mixture slowly warms to about 70° spontaneously. After two to three hours the mixture, which has started to cool, is filtered with suction, and the residue is washed twice with 100-cc. portions of hot alcohol

The filtrate is poured into five volumes of ice water acidified with about 425 cc. of concentrated commercial hydrochloric acid. The benzohydrol separates as a white crystalline mass and is filtered by suction. The yield of crude air-dried product melting at 65℃ is 194–196 g. (96–97 per cent of the theoretical amount). From 200 g. of crude product in 200 cc. of hot alcohol there is obtained, after cooling in an ice-salt mixture, filtering, and drying, 140–145 g. of product melting at 68℃. The benzohydrol remaining in the mother liquors may be precipitated with water.

三、金属氢化物还原

金属氢化物是还原羰基化合物为醇的首选试剂。这些方法具有对反应条件温和，副反应少以及产率高的优点，特别是某些烃基取代的金属化合物，显示了对官能团的高度选择性和较好的立体选择性。在复杂的天然产物的合成中，较之其他还原法显示出更多的优点。最常用的为氢化铝锂(LiAlH₄)、硼氢化钾（钠、锂）[K(Na,Li)BH₄]，以及发展了化学和立体选择性好的试剂，例如硫代硼氢化钠(NaBH₂S₃)、三仲丁基硼氢化锂LiBH (CH₃CH₂CH(CH₃))₃等。

3.1

反应机理

金属复氢化物具有四氢铝离子(AlH₄-)或四氢硼离子(BH₄-)的复盐结构，这种复合负离子具有亲核性，可向极性不饱和键中带正电的碳原子进攻，继而发生负离子转移而进行还原。反应在无质子溶剂中进行，则生成配合物，反应在质子溶剂中进行，则得醇。

氢化铝锂还原反应机理与硼氢化钠相同。由于四氢铝离子或四氢硼离子都有四个可供转移的负离子，还原反应可逐步进行，理论上1摩尔的硼氢化钠可还原4摩尔（好象是2摩尔）的羰基化合物。《药物合成反应》闻韧主编第二版化学工业出版社p379

3.2

试剂的主要性质及反应条件

类还原剂都是由两种金属氢化物之间形成复负氢离子的盐形式而存在。

不同的复氢金属还原剂的还原能力，以氢化铝锂最大，可被还原的功能基范围也很广泛，因而选择性较差。硼氢化锂次之，硼氢化钠（钾）较小。还原能力较小的还原剂往往选择性较好。此类还原剂的适应范围见下表:

注：表中+表示功能基能被还原，-表示不能被还原。

由于这类还原剂的反应活性和稳定性的不同，使用时反应条件也有所不同，氢化铝锂遇水，酸或含羟基，巯基化合物，可分解放出氢而形成相应的铝盐。因而反应需在无水条件下进行，且不能使用带有羟基或巯基的质子溶剂及可被还原的溶剂（DMF, DMSO, CH₂Cl₂）等。一般用醚类溶剂，主要是无水四氢呋喃或乙醚，其在乙醚中的溶解度为20-30%，四氢呋喃为17%。

氢化硼钾（钠）与上述锂盐有所不同，在常温下，遇水，醇都较稳定，不溶于乙醚及四氢呋喃，能溶于水，甲醇，乙醇而分解甚微，因而常选用醇类作为溶剂。如反应须在较高的温度下进行，则可选用异丙醇，二甲氧基乙醚等作溶剂。在反应液中，加入少量的碱，有促进反应的作用。硼氢化钠比其钾盐更具引湿性，易于潮解，故工业上多采用钾盐。采用氢化硼钾（钠）还原剂反应结束后，可加稀酸分解还原物并使剩余的氢化硼钾生成硼酸，便于分离。

用氢化铝锂还原剂反应结束后，可加入乙醇，含水乙醚或10%氯化铵水溶液以分解未反应的用氢化铝锂和还原物。用含水溶剂分解时，其水量应近于计算量，使生成颗粒状沉淀的偏铝锂而便于分离。如加水过多，则偏铝酸锂进而水解成胶状的氢氧化铝，并与水和有机溶剂形成乳化层，致使分离困难，产物损失较大。

因而，氢硼化物类还原剂，不能在酸性条件下反应，对于含有羧基的化合物的还原，通常应先中和成盐后再反应。

3.3

NaBH₄还原酮示例⁸

Reaction Scheme:

Procedure:

A. trans-9,10-Dihydro-9,10-phenanthrenediol (1). Phenanthrenequinone (6 g., 0.03 mole) is placed in a fritted-glass (coarse porosity) extraction thimble of a Soxhlet apparatus over a 1-l. flask containing a suspension of 3 g. of lithium aluminum hydride in 500 ml. of anhydrous diethyl ether. Extraction of the quinone over a period of 16 hours affords a green solution. The reaction is quenched by the cautious addition of water and neutralized with glacial acetic acid. The ether layer is separated, and the aqueous layer is extracted with two 200-ml. portions of ether. The combined ether extracts are washed consecutively with aqueous sodium hydrogen carbonate and water, then dried over magnesium sulfate. Evaporation of the solvent under reduced pressure gives the crude product, which is recrystallized from benzene, giving 3.8–4.1 g. (62–68%) of pure diol 1 as fluffy, white needles, m.p. 185–190℃.

3.4

LAH还原酮示例⁹

To a stirred solution of 3.1 g of 2-(3-oxo-n-butyl)-1,2,3,14b-tetrahydro-10H-pyrazino [1,2-a]pyrrolo[2,1-c][1,4] benzodiazepine (Example 24, No. 10) in 100 ml of diethyl ether is added 550 mg of lithium aluminumhydride in small portions.. The mixture is stirred at room temperature overnight, combined with 0.6 ml of water, 0.6 ml of 15percent aqueous sodium hydroxide and 0.6 ml of water in this order, filtered and evaporated. The residue is taken up in the minimum amount of isopropanol and the solution neutralized with fumaric acid, to yield the 2-(3-hydroxy-n-butyl)-1,3,4,14b-tetrahydro-10H-pyrazino [1,2-a]pyrrolo[2,1-c][1,4] benzodiazepine monofumarate melting at 181.deg.-183.deg.

四、醇铝还原剂还原（Meerwein-Ponndorf-Verley反应）

将醛，酮等羰基的化合物和异丙醇铝在异丙醇中共热时，可还原得到相应的醇，同时将异丙醇氧化为丙酮。这是仲醇用酮氧化反应的逆反应（Oppenauer反应）。

异丙醇铝是脂肪族和芳香醛，酮类的选择性很高的还原剂，对分子中含有的烯键，炔键，硝基，缩醛，腈基及卤素等可还原功能基无影响。

4.1

反应机理及影响反应的因素

异丙醇铝还原羧基化合物时，首先是异丙醇铝的铝原子与羧基的氧原子以配位键结合，形成六元环过渡态，然后，异丙基上的氢原子以负离子的形式从烷氧基转移到羰基碳原子上，得到一个新的醇-酮配合物，铝-氧键断裂，生成新的醇-铝衍生物和丙酮，蒸出丙酮有利于反应完全。醇-铝衍生物经醇解后得到还原产物，本步是决定反应步骤，因而反应中要求有过量的异丙醇存在。

本反应为可逆反应，因而，增大还原剂量及移出生成的丙酮，均可缩短反应时间，使反应完全。由于新制异丙醇铝是以三聚体形式与酮配位，因此酮类与醇-铝的配比应不少于1：3，方可得到较高的收率。

反应中加入一定量的三氯化铝，使生成的一部分氯化异丙醇铝，可加速反应并提高收率。因为氯化异丙醇铝与羰基氧原子形成六元环的过渡态较快，使氢负离子转移较易。

1，3-二酮，β-酮酯等易于烯醇化的羰基化合物，或含有酚性羟基等酸性基团的羰基化合物，其羟基易于与异丙醇铝形成铝盐，使还原反应受到抑制，因而，一般不采用本法还原。含有氨基的羰基化合物，也易与异丙醇铝形成复盐而影响还原反应进行，但可改用异丙醇钠为还原剂。

4.2

LiAlH(OPr-i)₃还原酮示例¹⁰

To dehydrated diethyl ether (12.6 ml) was added lithium aluminum tri-tert-butoxyhydride (457 mg), and the resulting mixture was cooled to -20.deg. C. followed by dropwise addition of a diethyl ether solution (5.3 ml) of (3R)-3-tert-butoxycarbonylamino-1-chloro-4-phenyl-2-butanone (500 mg).The resulting mixture was stirred at -20.deg. C. for 6 hours.To the reaction solution was added aqueous 5percent potassium hydrogen sulfate solution, to quench the reaction, which was then subjected to extraction twice in ethyl acetate; the organic layer was washed by aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate.After removal of magnesium sulfate, the resulting ethyl acetate solution was analyzed by HPLC. It was confirmed that the diastereomer mixture of 3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutazone was obtained in 90percent yield.The ratio of the objective (2S, 3R) compound and the isomer (2R, 3R) was (2S, 3R): (2R, 3R)=76.9:23.1. The solvent was evaporated from the resulting solution under reduced pressure, to afford crude (2S, 3R)-3-tert-butoxycarbonylamino-1-chloro-2-hydroxy-4-phenylbutane (0.502 g) in solid .

4.3

LiAlH(OBu-t)₃还原酮示例¹¹

A. 3β-Acetoxy-20β-hydroxy-5-pregnene. In a 2-l. five-necked flask fitted with a mechanical stirrer, 250-ml. dropping funnel, thermometer, nitrogen-inlet tube, and reflux condenser with calcium chloride tube is placed 750 ml. of anhydrous tetrahydrofuran. The vessel is flushed with nitrogen, and 101.6 g. (0.4 mole) of lithium aluminum tri-t-butoxyhydride is added. The suspension is cooled to about 2℃, and 71.7 g. (0.2 mole) of pregnenolone acetate is added in one portion while stirring, the particles adhering to the wall of the flask being rinsed into the solution with an additional 50 ml. of tetrahydrofuran. The reaction mixture is stirred at 0–5℃for 6 hours. A solution of 100 g. of ammonium sulfate in 150 ml. of water is added, with stirring, over a 15–20 minute period through the dropping funnel, the temperature of the reaction mixture being kept below 10℃ by efficient cooling with ice. A considerable quantity of hydrogen is evolved. There is added 20 g. of filter aid (Celite^® or Hyflo Supercel^®), the mixture is stirred for another 30 minutes, and it is finally filtered with suction through a layer of filter aid. The reaction vessel is rinsed and the filter residue thoroughly washed with 1.5 l. of tetrahydrofuran. The filtrate is evaporated to dryness under reduced pressure. The crystalline residue is dissolved in 750 ml. of hot acetone, filtered (if necessary), and the solution is concentrated to a volume of about 200 ml. (crystallization may begin during this evaporation). The flask is kept overnight at 0℃ to −10℃ and the product isolated by suction filtration. The crystals are washed with 75 ml. of ice-cold acetone and dried at 60°. The yield of the product is 54–57 g. (75–79%), m.p. 161–164℃^. [α]²⁵D −74° (c 1.0, CHCl₃).