酮还原成亚甲基

2020-03-30 来源：年旅网

经典化学合成反应标准操作

酮还原成亚甲基

编者：韦昌青

药明康德新药开发有限公司化学合成部

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经典合成反应标准操作—酮还原成亚甲基反应药明康德新药开发有限公司

1． 2． 3． 4． 5． 6． 7． 8．

前言 ……………………………………………………………………2 Clemmensen 还原……………………………………………………5 Wolff-Kishner-黄鸣龙还原…………………………………………8 Et3SiH-BF3 或Et3SiH-TFA法还原 …………………………………11 LAH-AlCl3或LAH 法还原 …………………………………………12 催化氢化法还原………………………………………………………14 NaBH4-TFA法还原 …………………………………………………17 酮或醛衍生化后还原…………………………………………………18

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1．前言

化学化学方法将醛或酮的羰基直接转化为亚甲基有如下几种：1) Clemmensen 还原; 2) Wolff-Kishner-黄鸣龙还原; 3) LiAlH4-AlCl31法; 4) NaBH4-CF3CO2H2法; 5) Et3SiH-BF3 or CF3CO2H3-5法; 6) HI-Phosphorus6-7法；7) 催化氢化法8.

催化氢化转化羰基为亚甲基由Brieger9-10组报导，他们使用Pd/C作为催化剂，并用FeCl3作Lewis酸促进剂. 另外,有综述11专门提到用甲酸铵作催化氢化转移剂.

近期,哈佛的Andrew Myers11在其关于腙衍生物工作中报导了用Sc(OTf)3作催化剂的有效的低温Wolff-Kishner还原.

对于有些结构复杂，带有多种敏感官能团时，以上这些一步或一锅法无法将醛或酮的羰基直接转化为亚甲基，因此可能需要将醛或酮转化为其他官能团进行除去。较为常见的方法是转化为醇羟基除去（醇羟基除去方法见脱羟基反应部分）；另外，可以将醛或酮转化为乙二硫醇的缩醛或酮，再用Raney Ni 氢化还原为亚甲基；另外也有文献将醛或酮转化为对甲苯磺酰肼的腙，再用DiBAL或NaBH(OAc)3还原。

OH还原脱羟基R1R2

OR1

HSSHSR1

SR2

H2, Raney Ni

rL oADIB)Ac3O(BHa NHH

OOSNR1

NHR2

Reference

1. J. Blackwell and W.J. Hickinbottom; J. Chem. Soc., 1961, 1405 2. G.W. Gribble, W.J. Kelly and S.E. Emery; Synthesis, 1978, 763

3. J.L. Fry, M. Orfanopoulos, M.G. Adlington, W.P. Dittman and S.B. Silverman; J. Org. Chem., 1978, 43,

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4. C.T. West, S.J. Donnelly, D.A. Kooistra, H.P. Doyle; J. Org. Chem., 1973, 38, 2675 5. D.N. Kursanov, Z.N. Parnes and N.M. Loim; Synthesis, 1974, 633 6. C. Bradsher and F. Vingiello; J. Org. Chem., 1948, 13, 786 7. R. Reimschneider and H. Kassahn; Ber., 1959, 92, 1705

8. R.L. Augustine; Catalytic Hydrogenation, Dekker, New York, 1965 9. G. Brieger, T.J. Nestrick and T.N. Fu; J. Org. Chem., 1979, 44, 1876 10. G. Brieger and T. H. Fu; J. Chem. Soc. Chem. Commun., 1976, 757 11. S. Ram and R.E. Ehrekaufer; Synthesis, 1988, 91 12. Andrew Myers et al J. Am. Chem. Soc. 2004, 126, 5436

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2. Clemmensen 还原

将醛或酮用锌汞齐处理在浓盐酸下加热可以将醛或酮的羰基转化为亚甲基. 这就是克莱门森（Clemmensen）还原1-7. 很明显,对酸敏感的底物（醛酮）不能使用此法还原（如醇羟基、C=C等）。

Zn-Hgconc. HCl

HRHR'

此法对于还原芳香酮和双烷基酮有一定的通用性。其用在还原芳香酮是间接在芳环上引入直链烃基的方法之一。

O+

conc. HCl

AlCl3

OZn-Hg

反应机理

反应发生在锌催化剂表面. 由于将相应的醇用于此反应条件并不能得到亚甲基化合物,因此该反应中间态可能没有醇产生. 下图大致描述了克莱门森（Clemmensen）还原的机理.

2.1 Clemmensen 还原芳基酮示例8

OOHOZn-HgHCl,H2OToluene

OOH

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Amalgamated zinc is prepared by shaking for five minutes a mixture of 120 g. of mossy zinc, 12 g of mercuric chloride, 200 mL of water, and 5–6 mL of concentrated hydrochloric acid contained in a 1-L round-bottomed flask. The solution is decanted and the following reagents are added, in the order named, to the zinc: 75 mL of water, 175 mL of concentrated hydrochloric acid, 100 mL of toluene, and 50 g (0.28 mol) of β-benzoylpropionic acid. The flask is fitted with a vertical condenser connected to a gas absorption trap, and the reaction mixture is boiled vigorously for twenty-five to thirty hours. Three 50 mL portions of concentrated hydrochloric acid are added at approximately six-hour intervals during the refluxing period. After cooling to room temperature the layers are separated. The aqueous layer is diluted with 200 mL of water and extracted with three 75 mL portions of ether. The toluene layer and the ether extracts are combined, washed with water, and dried over calcium chloride. The solvents are removed by distillation under reduced pressure on the steam bath, after which the χ-phenylbutyric acid is distilled at 178–181°/19 mm. (148–154°/8–10 mm., 125–130°/3 mm.). The yield of acid, which melts at 46–48°, is 38–41 g. (82–89%).

2.2 Clemmensen 还原二烷基酮示例9

OF3C

OOZn-Hg

F3C

OOH

Clemmensen reduction of methyl 8,8,8-trifluoro-4-ketooctanoate was carried out in a 2-liter, three neck, round-bottom flask fitted with a Liebig condenser surmounted by a Friedrichs condenser, a Hershberg stirrer with a Trubore bearing, and a 50-mL dropping-funnel. The condensers were sealed with a Dry-Ice trap, and a gas washing bottle filled with petroleum ether (65-110 oC). The flask was charged with 300 g. of amalgamated, reagent grade, mossy zinc, 100 mL of water, 240 mL of concentrated hydrochloric acid, and 93.0 g (0.41 mole) of methyl 8,8,8-trifluoro-ketooctanoate. The mixture was heated with an oil-bath at 120-130

C. The reactiori was continued for 112 hours, and an additional 50 g. of amalgamated zinc

and 50 mL of concentrated hydrochloric acid were added every 24 hours. The reaction mixture was extracted with four portions of isooctane, and then the extract was washed with water and dried by azeotropic distillation with ethylene chloride. Fractional distillation of the residue through a Vigreux partial take-off, fractionating column yielded two main fractions: ω-trifluorooctanoic acid, 31.6 g. (72%, converted keto acid), b.p. 129 oC (10 mm.);

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and 8,8,8-trifluoro-4-ketooctanoic acid, 36.0 g., b.p. 136 oC.

Reference

1. E. Clemensen, Ber.,1913, 46, 1837.

2. S. Yamamura, S. Ueda, Y. Hirata, Chem. Commun., 1967, 1049. 3. S. Yamamura, Y. Hirata, J. Chem. Soc.,C, 1968, 2887. 4. S. Yamamura, Chem. Commun., 1968, 1494. 5. S. Yamamura, Tetrahedron Lett., 1967, 3361.

6. M. Toda, Y. Hirata, S. Yamamura, Chem. Commun., 1969, 919. 7. E. Vedejs, Org. React. (N.Y.), 1975, 22, 401. 8. Organic Syntheses, Coll. Vol. 2, p.499; Vol. 15, p.64

9. Gilbert Gavlini and Richard G. Maguire J. Org. Chem. 1956, 21, 1342-1346

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３. Wolff-Kishner-黄鸣龙还原

醛类或酮类在碱性条件下与肼作用，羰基被可以被还原为亚甲基1-13。此反应是Kishner (吉尔聂尔, 俄国人) 和Wokff (沃尔夫, 德国人)分别于1911、1912年发现的，故此而得名。原来Wolff-Kishner的方法是将醛或酮与肼和金属钠或钾在高温(约200 °C)下加热反应，需要在封管或高压釜中进行。另外,此法要用金属钠以及难以制备和价值昂贵的无水肼。同时在应用此法还原时，若有极少量的水份存在，往往不可避免地要引起一些副反应。虽曾有人对此法进行过改良，但效果不显著。

OH2NNH2-H2O

NNH2

KOH-N2

1946年，黄鸣龙3对此法进行了卓有成效的改进。经他改良的方法，只需将酮类和醛类与氢氧化钾和氢氧化钠(代替金属钠)，85%(有时可用50%)水合肼(代替无水肼)及双缩乙二醇或三缩乙二醇(代替封管或高压釜)，同置于圆底烧瓶内，回流1小时，移去冷凝管，继续加热，直到溶液温度上升至190-200 oC时，再插上冷凝管，保持此温度23小时，然后按常规方法处理即得。若被还原的物质还原后的生成物沸点低于190-200 oC，则在蒸去水分时，物质亦随之逸去，故必须在冷凝管与烧瓶间装一分液管，借以除去水分。例如：

NH2NH2.H2O

ONaOH+

(HOCH2CH2)2ON2

200℃3~5h

82%

该法可同时适用于芳基和烷基酮的合成，但对碱或高温条件敏感的化合物不适合用此法还原。

反应机理

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3.1 黄鸣龙还原芳基酮示例3

OH2NNH2.H2O

A mixture of 18.2 g of benzophenone, 7 g of sodium hydroxide, 100 mL of triethylene glycol and 10 mL of 85% hydrazine hydrate was refluxed for 1 h. Then the condenser was removed until the temperature of the solution was had reached 195~200 oC, when refluxing was continued for about three hours. The mixture was cooled and extracted with ether. The ether residue on distillation over sodium gave 14.0 g (83.3%) of pure hydrocarbon, b. p. 149 oC at 29 mmg.

3.2 黄鸣龙还原二烷基酮示例14

OH2NNH2.H2ONadiethylene glycol

170 oC

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A reaction with 14.2 g (0.1 mol) of the ketone, 9 mL (0.18 mol) of hydrazine hydrate, 20 g of sodium and 400 mL of dithethlene glycol was carried out at 170-190 o for sixty-eight hours. After dilution with water, extraction with ether. The organic layer was washed in turn with water, dilute hydrochloric acid, and again with water. The extract was dried over anhydrous magnesium sulfate. Removal of solvent left the crude hydrocarbon, which was redistilled over sodium to give 8.95 g (70 %) of 2,6-dimethylheptane, bp 131-133o.

Reference

1. N. Kishner, J. Russ. Phys. Chem. Soc. 43, 582 (1911); C.A. 6, 347 (1912) 2. L. Wolff, Ann. 394, 86 (1912)

3. Huang Minlon J. Amer. Chem. Soc. 68, 2487 (1946) 4. D. Todd in Organic Reactions IV, 378 (1948) 5. V. Franzen, Chem. Ztg. 80, 667 (1956)

6. R. A. Braun and W. A. Mosher, J. Amer. Chem. Soc. 80, 4919 (1958) 7. D. H. R. Barton, D. A. J. Ives and B. R. T. Thomas, J. Chem. Soc. 1955, 2056 8. J. H. Weisburger and P. H. Grantham, J. Org. Chem. ,1160 (1956)

9. V. Georgian, R. Harrisson and N. Gubisch, J. Amer. Chem. Soc. 81, 5834 (1959) 10. D. J. Cram, M. R. V. Sahyun d G. R. Knox, J. Amer. Chem. Soc. 84, 1734 (1962) 11. S. Hunig and W. Eckardt, Ber. 95, 2498 (1962)

12. M. F. Grundon, H. B. Henbest and M. D. Scott , J. Chem. Soc. 1963, 1855 13. H. H. Szmant and C. M. Harmuth, J. Amer. Chem. Soc. 1964 86, 2909 14. Soffer J. Am. Chem.Soc. 1945, 67, 1435-1436

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4. Et3SiH-BF3 或Et3SiH-TFA法

一般而言，该方法主要用于芳基酮或二芳基酮的还原

4.1 Et3SiH-BF3还原示例1

OO2N

Et3SiH.BF3CH2Cl2, 0 to 25 oC

O2N

A dry, 250-mL, three-necked, round-bottomed flask is equipped with a magnetic stirring bar, a gas-inlet tube, a pressure-equalizing dropping funnel, and a Dewar condenser cooled with ice-water and fitted with a drying tube containing anhydrous calcium sulfate (Drierite). A solution of 20.9 g (0.180 mol) of triethylsilane in 80 mL of dichloromethane is placed in the flask. The solution is stirred rapidly and cooled in an ice bath while boron trifluoride gas is introduced below the surface of the liquid at a moderate rate. The first appearance of white fumes at the exit of the drying tube indicates that the solution is saturated and the apparatus is filled with boron trifluoride. The flow of boron trifluoride is adjusted to a level sufficient to maintain a slight emission of white fumes from the drying tube, and a solution of 10.0 g (0.0606 mol) of m-nitroacetophenone in 30 mL of dichloromethane is added dropwise during 10 min. Stirring and cooling are continued for 30 min, after which the flow of boron trifluoride gas is stopped and the cooling bath is removed. The mixture is stirred at room temperature for 20 min, cooled again with the ice bath, and hydrolyzed by adding 20 mL of aqueous saturated sodium chloride. The upper organic layer is decanted from the salts, which are then dissolved in 50 mL of water. The aqueous solution is extracted with two 25 mL portions of pentane, which are combined with the original organic layer. The organic solution is washed with two 25 mL portions of saturated sodium chloride and dried with anhydrous sodium sulfate. Distillation at atmospheric pressure through a 10-cm Vigreux column serves to separate solvent and ca. 15 g of a mixture of primarily triethylsilane and triethylfluorosilane, bp 106–109°C. The remaining liquid is distilled in a short-path distillation apparatus under reduced pressure, affording 8.33–8.38 g (91–92%) of pale yellow m-nitroethylbenzene, bp 120–121°C (15 mm), 134–135°C (22 mm), nD25 1.5330.

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4.2 Et3SiH-TFA 还原示例2

NO2

H2NO2N

TFA, MeNO2

Et3SiH

H2NO2N

2NO2

To a solution of 1 (2 g, 6.97 mmol) in CF3COOH (7 mL) and MeNO2 (5 mL) (to aid solution) was added Et3SiH (2 g) over 5 min. The mixture was stirred at room temperature for 96 h, after which time a yellowish precipitate had formed on the sides of the flask. Acetone (20 mL) was added to dissolve the precipitate, followed by 30 mL of H2O, and the solution clarified. The filtrate was basified at 15 oC to pH 8 with concentrated NH4OH, and the resultant precipitate filtered, washed with water, and dried, followed by re-crystallization from anhydrous Et2O. This produced 1.86 g (98%) of 2 as a yellow powder: mp 82-84 oC; MS (M+) 273; 1H NMR (80 MHz, CDC1,) δ 3.96 (s, 2, CH2), 7.24 (m, 5, C6H5), 8.37 (br s, 4, NH2 and 2,6-H2).

Reference

1. Organic Syntheses, Coll. Vol. 7, p.393; Vol. 60, p.108

2. Kwasi A. Ohemengt and Barbara Roth J. Med. Chem. 1991,34, 1394-1399

5. LAH-AlCl3 或 LAH 法还原

一般而言，该方法主要用于芳基酮或二芳基酮的还原 (????). 如芳环上带有许多富电子基团或二芳基的酮，这类还原易于进行有时不需要加任何Lewis 酸.

5. 1 LAH-AlCl3法示例1

OLAH, AlCl3ether

A solution of AlCl3 (106.7 g, 0.8 mol) in diethyl ether (200 mL) was added slowly to a stirred

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slurry of LiAlH4 (15.2 g, 0.4 mol) in ether (100 mL), and the mixture was stirred for 5 min. A solution of 4-methylbenzophenone (49.1 g, 0.25 mol) was then added dropwise, while the reaction mixture was stirred. The exothermic reaction kept the mixture refluxing. When the refluxing stopped, the mixture was stirred for another 15 min, and ethyl acetate (53 mL, 0.55 mol) was added dropwise to decompose excess reagent. The mixture was poured onto ice (300 g) and NH4Cl (85 g), and the ethereal layer was separated and washed with saturated sodium chloride solution (100 mL). The aqueous layer was extracted with dichloromethane (2*100 mL), the extracts were combined with the ether solution and driedwith MgSO4, and the solvent was evaporated. The crude product was distilled under vacuum (bp 112 oC/0.05 Torr) to yield a pure colorless liquid (42.9 g, 94%). 'H NMR (60 MHz, CDCI,) δ 2.31 (s, 3 H, CH,), 3.95 (s, 2 H, CH2), 7.10 (s, 4 H, arom), 7.23 (m, 5 H, arom); MS m/z (re1 intensity) 182 (M+, 74), 181 (18), 167 (IOO), 166 (24), 165(47), 152 (18), 91 (10).

5.2 LAH直接还原二芳基酮示例2

OLAHNH2NH2

A solution of benzophenone (42 g, 0.2 mol) in ether (400 mL) was added dropwise to a solution of lithium aluminum hydride (35.6 g, 0.93 mol) in ether (1400 mL) and the mixture was bolied under reflux for 6 g. The solution was cooled. Then 36 mL of water was added dropwise. The solid was removed and filtrate was concentrated and the risidue distilled (bp 88-90 at 0.027 mmHg) to afford the product (22 g, 61 %), which on collong solidified; mp 30-32 o

Reference

1. Roman Popielarz and Donald R. Arnold J . Am. Chem. Soc. 1990, 112, 3068-3082 2. Wardrop, J. Chem. Soc. Perkin Trans.1 1976, 1279-1285

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6. 催化氢化法

一般来说，芳环α-位的酮或醛直接还原到亚甲基并不是很容易的事，但对于某些特殊的酮而言是可以的，如芳环上带有许多富电子基团或二芳基的酮，这类氢化相对易于进行，但一般也要在醋酸中或加入酸催化剂进行反应。

6.1 以甲酸胺为氢源催化氢化还原芳基酮示例1

OR3R2R1R410% Pd/C, HCO2NH4R3R2R1R4

To a stirred suspension of an appropriate aldehyde or ketone (7.5 mmol) and 10% Pd/C (0.350 g) in glacial acetic acid (10 mL), the anhydrous ammonium formate (38 mmol) was added in a single portion under argon. The resulting reaction mixture was stirred at 110oC for 10-30 min. The progress of reaction was monitored by TLC and GC. After completion of the reaction, 50 mL of CHCl3 was added, and the catalyst was removed by filtration through a celite pad and washed with CHCl3 (20 ml). The combined organic filtrate was washed with water (20 mL* 2), then with saturated sodium bicarbonate solution (20 mL* 2), and dried over anhydrous Na2SO4. The organic filtrate on evaporation, either under reduced pressure or at normal pressure, afforded the desired product, which was further purified by column chromatography over silica gel using an ethyl acetate/hexane mixture as the mobile phase. The phenolic derivatives were obtained by direct evaporation of filtrate after removal of the catalyst. The results listed in Table 1.

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6.2 盐酸催化下氢化还原富电子芳基酮示例2

OROR=H, CH3, C2H5, C3H7

H2, Pd/C

OOR

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2,4-dimethoxyphenyl alkyl keton (0.1 mol) was dissolved in ethanol (300 mL) and was hydrogenated at NTP in the presence of conc. HCl (1 mL) and Pd/C (5 %, 2.0 g). When the absorption of hydrogen ceased, the catalyst was filtered off. The solvent was removed to give 2,4-dimethoxylphenylalkyl benzene as an oil.

6.3 醋酸催化下氢化还原富电子芳基酮示例3

OH2

RR2

COOHR1

Pd/C,HOAc

COOHR1

A solution of 0.01 mol of the appropriate 2-(aroyl)arylacetic acid in 35-40 mL of glacial AcOH was shaken under an initial 3 atm of H2 at 50-60 OC, using 5% Pd on charcoal (0.2 g) as catalyst. After 7 h, the reaction mixture was filtered, and the filtrate, after concentration under reduced pressure, was diluted with HzO. The crystalline precipitate was collected by filtration and dried. Purification, when required, was accomplished by crystallization from an EtOH-H20 (see Table II).

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Reference

1. Tetrahedron Lett. 1988, 29(31), 3741-3744

2. Tomas de Paulis et al J.Med. Chem. 1985, 28, 1263-1269

3. Giovanni Brancaccio, Angelo Larizza, Guglielmo Lettieri, J. Med. Chem. 1981,24, 998-1000

7. NaBH4-TFA还原二芳基酮为亚甲基

该法主要用于二芳基酮的合成

7.1 NaBH4-TFA还原二芳基酮为亚甲基示例

该法主要用于二芳基酮的合成

OCF3CO2HNaBH4

X=H, Z=HX=H, Z=CH3X=H, Z=OCH3X=H, Z=ClX=H, Z=CNX=OCH3, Z=HX=OCH3, Z=CH3X=OCH3, Z=OCH3X=OCH3, Z=ClX=OCH3, Z=CN

To magnetically stirred trifluoroacetic acid (50 mL) at 0 oC under nitrogen, sodium borohydride (2.0 g, 53 mmol) was carefully added in portion over 45 min. To this slurry a solution of substrate (10 mmol) in dry dichloromethane (40 mL) was added dropwise. As each drop of solution comes in contact with the slurry, a strong coloration (the carbocation) was observed which rapidly disappeared. The rate of addition is governed by the rate of color discharge. After the mixture was stirred at room temperature under nitrogen for typically 20 h, it was quenched with ice cooled aqueous 2 M sodium chloride until alkaline. After extraction into dichloromethane (3*60 mL), the separated organic layers were combined

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and washed with saturated sodium carbonate (100 mL). The organic layer was dried over anhydrous magnesium sulfate for 3 h. After filtration the dichloromethane was evaporated off, giving a crude solid witch was re-crystallized from ethanol or propan-2-ol.

Reference

1. James H. P. Utley and Gregor G. Rozenberg Tetrahedron, 2002, 58, 5251-5265

8. 酮或醛衍生化后还原为亚甲基

8.1 醛或酮转化为乙二硫醇的缩醛或酮，再用Raney Ni 氢化还原为亚甲基示例

OOOHNOHSBF3

SHHN

SSOOORaney-Ni

HNOOO1

To a mixture of 1 (2.0 g), acetic acid (30 mL) and ethanedithiol (2 mL) was dropwise added BF3-ethrate (4 mL) at room temperature. The reaction mixture was allowed to stand at room temperature for 6 hr. Ice-water was added and extracted with ether and CHCl3. The combined organic layers washed with NaHCO3 solution until acetic acid was removed, then washed with H2O, dried over Na2SO4. Evaporation of the solvent afforded an oil, which crystallized on standing. Re-crystallization on from EtOH afforded 1.85 g of 2 as needles, mp 134-136 o.

A mixture of 2 (650 mg), Raney Ni (0.9 g) and abs. EtOH (75 mL) was heated under reflux

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经典合成反应标准操作—酮还原成亚甲基反应药明康德新药开发有限公司

for 7 hr. Then, the catalyst was filtered off and washed with EtOH. The combined filtrates were evaporated under reduced pressure to dryness to give an oil (513 mg), which was dissolved in EtOH (10 mL) and stirred with Raney Ni (300 mg) in hydrogen atmosphere for 4 hr. The catalyst was filtered off and washed with EtOH and filtrates were evaporated under reduced pressure to dryness to give an oil (513 mg). This oil was purified via chromatography (benzene/CHCl3 1:1) gave pure 3 (212 mg, 48 %).

8.2 将醛或酮转化为对甲苯磺酰肼的腙，再用DiBAL还原示例

2OONH2SNHMeOH

OO3

NSNHODiBALCH2Cl2

The ketone 1 (851 mg, 5 mmol) was heated briefly to boiling with 931 mg (5 mmol) of p-toluenesulfonylhydrazine in 5 mL of methanol. After 24 h at room temperature, the reaction mixture was evaporated to dryness under reduced pressure and washed with pentane to give a crystalline product, 1.7 g (l00 %), mp 190-191 oC. NMR (CDCl3) δ 2.38 (s, 3 H, ArCH3), 3.00 (s, 3 H, OCH3), 3.16 (s, 3 H, OCH3), 7.20 (d, J = 8 Hz, 2 H, ArH), 7.74(d, J = 8 Hz, 2 H, ArH).

To 3 (338 mg, 1 mmol) in 2 mL of dry CH2C12 was added at 0 oC under N2 2.5 mL of 0.9 M diisobutylaluminum hydride (DBAL) in hexane. The mixture turned bright yellow after ca. 1 mL of the DIBAL solution was added, and all the tosylhydrazone was dissolved during DIBAL addition. Stirring was continued for 15 min (subsequent reactions showed no increase in yield with extended reaction times), and the solution was carefully decomposed with 2.5 mL of 3 N aqueous NaOH. Extraction with pentane, drying (MgSO4), and distillation of the solvents through an efficient Vigreux column gave a colorless solution containing 103 mg (66%) of 7,7-dimethoxybicyclo[2.2.1] heptane by GC analysis on column

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B, 80-100 oC. A sample of the product was purified by preparative GC on column D (110

C). It had NMR (CC14) δ 0.9-1.4 (m, 4 H), 1.5-2.0 (m, 6 H), and 3.10 (s, 6 H, 2 OCH3)

ppm and MS m/e (rel intensity) 156 [M+], 101 (100).

8.3 Sc(OTf)3催化下, 用TBS-NH-NH-TBS与酮或醛成腙后还原为亚甲基示例

近来, 哈佛的Andrew Myers在其关于腙衍生物工作中报导了有效的低温Wolff-Kishner还原. 在Sc(OTf)3催化下, 用TBS-NH-NH-TBS与酮或醛成腙, 再加入tBuOH/tBuOK 在DMSO中可将粗品腙进行有效的低温Wolff-Kishner还原成10. 另外, 可以对酮腙卤化可得烯卤化物如 11, 或根据不同的条件制得 1,1-二卤化物. 对醛腙卤化可得1,1-二卤化物如13.

Reference

1. Trtsuo Hiraoka and Yukichi Kishida Chem. Pharma Bull. 1968, 16, 1576-1583

2. David A. Lightner, Jacek K. Gawrohski, and Thomas D. Bouman, J. Am. Chem.Soc. 1980，102，1983-1990

3. Michael E. Furrow and Andrew G. Myers J. Am. Chem. Soc. 2004, 126, 5436-5445

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