有机合成英文文献翻译2

Organic Syntheses, Vol. 81, p. 254-261 (2005); Coll. Vol. 11, p. 874-878 (2009).

254 PREPARATION OF PIVALOYL HYDRAZIDE IN WATER (Propanoic acid, 2,2-dimethyl-, hydrazide)

2 +NaOH/H2O

H2NNH2 · H2O

Submitted by Bryan Li,1Raymond J. Bemish, David R. Bill, Steven Brenek, Richard A. Buzon, Charles K-F Chiu and Lisa Newell.

Checked by Claire Coleman and Peter A. Wipf.

1. Procedure

Pivaloyl hydrazide. A 1-L, three-necked, round-bottomed flask equipped with a T eflon-coated thermocouple and mechanical stirrer is charged with 400 mL of water and sodium hydroxide (12.87 g, 322 mmol), and the resulting mixture is stirred until all of the solids dissolve (Note 1). Hydrazine (35% aqueous solution, 36.83 g, 400 mmol) is then added in one portion. T he mixture is cooled in an ice-water/acetone bath to an internal temperature of –5 to 0 °C, and trimethylacetyl chloride (38.6 mL, 320 mmol) is added dropwise (Note 2) over a period of 40-60 min while maintaining the reaction temperature between –5 and 0 °C (Note 3). T he reaction mixture is then transferred to a 1-L, pear-shaped flask and concentrated to a volume of ca. 100 mL by rotary evaporation (at ca. 100 mm) (Notes 4, 5) and the resulting suspension is filtered (Note 6). T he filtrate is further concentrated to a volume of ca. 40 mL (Note 7) and 100 mL of toluene is then added. The resulting solution is transferred to a three-necked, round-bottomed flask equipped with a Dean-Stark water separator, thermometer, and rubber septum. Distillation is continued at atmospheric pressure until a constant boiling point is reached (Note 8) and then the pot volume is further reduced to ca. 40 mL. The resulting heterogenous mixture is filtered (Note 9) and the filtrate is concentrated by rotary evaporation under reduced pressure to provide the desired product as a colorless oil,

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which on sta nding solidifies to a white semi-solid. This ma teria l is recrysta llized from 100 mL of isopropyl ether to a fford 18.6-20.4 g (50-55%) of pivaloyl hydrazide (Notes 10, 11).

2. Notes

1. All rea gents were purcha sed from Aldrich Chemica l Compa ny (except for trimethyla cetyl chloride, which the checkers obta ined from Acros) and were used without further purification. The checkers used a low temperature alcohol thermometer in place of a Teflon-coated themocouple. The third neck of the flask was left open to the atmosphere.

2. A syringe pump was used for the addition of acid chloride in order to achieve a steady flow rate. The tip of the syringe needle (gauge 20) was submerged in the rea ction mixture. Dropwise a ddition of trimethyla cetyl chloride at 0-5 °C resulted in the immediate formation of a precipitate.

3. The rea ction wa s complete a t the end of the piva loyl chloride addition. On 5-L or larger scale, the reaction was conducted at temperatures of 10-15 °C without loss of selectivity.

4. A small a mount of hydrazine hydrate was present in the reaction mixture a t this point, but a sa fety eva lua tion indica ted the fina l rea ction mixture ha d a very low therma l potentia l (DH=1

5.3 J/g). This poses a minimum thermal hazard for vacuum distillation.

5. The submitters concentra ted the rea ction mixture by va cuum distilla tion (100 mm, ba th tempera ture 70 °C, va por tempera ture 51 °C). The weight a fter concentra tion wa s ca. 120 g. The checkers used rota ry evaporation with a bath temperature of 65 to 70 °C without any problems, and employed an explosion shield as a safety precaution.

6. The bis-a cyl a tion byproduct (Me 3CCONHNHCOCMe 3) w a s removed by filtration; 20 mL of water was used for washing the filter cake.

7. The submitters removed solvent by vacuum distillation (100 mm, bath temperature 70 °C, vapor temperature 51 °C).

8. Azeotropic remova l of wa ter wa s complete when the va por temperature reached 111 °C.

9. Sodium chloride was removed by filtration.

10.T he submitters obtained the product in 72% yield without recrystallization and determined the product to be >97% pure by HPLC (by area; conditions: 250 mm Kromasil C4 column using acetonitrile (A)/water

(B) and 0.1% TFA in water (C), 0:90:10 A:B:C ramp to 90:0:10 A:B:C over

15 min and hold for 5 min.

Waste Disposal Information

All toxic materials were disposed of in accordance with “Prudent Practice in the Laboratory”; National Academy Press; Washington, DC, 1995.

3. Discussion

Hydrazides (RCON HN H2) are highly useful starting materials and intermediates in the synthesis of heterocyclic molecules.2 They can be synthesized by hydrazinolysis of amides, esters and thioesters.3 The reaction of hydrazine with acyl chlorides or anhydrides is also well known,4 but it is complicated by the formation of 1,2-diacylhydrazines, and often requires the use of anhydrous hydrazine which presents a high thermal hazard. Diacylation products predominate when hydrazine reacts with low molecular weight aliphatic acyl chlorides, which makes the reaction impractical for preparatory purposes.5

Recently we needed to prepare large amounts of pivaloyl hydrazide (1). A literature survey indicated several approaches: (1) heating pivalic acid with hydrazine hydrate with a Lewis acid catalyst such as activated alumina6 or titanium oxide;7 (2) heating hydrazine hydrate at high temperature (140 °C) with ethyl pivalate;8 (3) condensing phthaloyl hydrazine with pivaloyl chloride, followed by deprotection of the phthaloyl group;9 and (4) reaction of ethyl thiopivalate with hydrazine hydrate. Reaction safety evaluations revealed that hydrazine monohydrate has an onset temperature of ca. 125 °C in a Differential Scanning Calorimetry (DSC) experiment, and possesses a very high thermal potential ( H = 2500 J/g),10,11 which prompted us to develop a method for the synthesis of 1 that did not require heating. After some experimentation we determined that the reaction of pivaloyl chloride with hydrazine proceeds most efficiently in water to give a 4:1 ratio12 of 1 to Me3CCONHNHCOCMe3(2). The use of organic solvents (MeOH, THF, 2-propanol) with water13 invariably led to formation of biphasic mixtures and predominant formation of 2.14 Reaction workup is also simplified using

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water as solvent. Upon partial concentration the bis-acylhydrazide by

product 2precipitated out of the reaction mixture and is conveniently

removed by filtration. Removal of the remainder of the water by

displacement with toluene leads to precipitation of NaCl, which is also

easily removed by filtration. The filtrate is then further concentrated to

provide 1 in >97% purity, typically in 55–75% yield. This procedure has

been employed to prepare 10 Kg batches of 1 with no difficulty.

译文：

在水相中制备特戊酰氯 （丙酸，2,2-二甲基酰肼）

论文由Bryan Li, Raymond J 、Bemish, David R 、Bill, Steven Brenek,Richard A 、Buzon, Charles K-F Chiu 和 Lisa Newell 等发表，经Claire Coleman 与Peter A. Wipf 审核。

1.1.步骤步骤步骤

特戊酰氯合成：将一升的三颈圆底烧瓶配备一个有特氟龙涂层的热电偶和机械搅拌器，装上400mL 水和氢氧化钠（12.87g,322mmol ）,将产生的混合物搅拌，直至所有固体全部溶解（注解1）。随后加入部分酰肼（35％水溶液，36.83克，400毫摩尔）。用冰水/丙酮浴将该混合物冷却到内部温度为–5～0℃，连续滴加（注解2）三甲基乙酰氯（38.6mL,320mmol)40～60分钟，同时保持反应温度在–5～0℃（注解3）。反应混合物随后用旋转蒸发仪（在约100mL ）转移到一个一升的梨形烧瓶中，收集到体积约100mL ，并将产生的悬浮物过滤（注解6），滤液进一步浓缩体积到40毫升（注解7），然后加入100毫升甲苯。将产生的溶液转移到一个配备有迪安-斯达克水分分离器，温度计和橡胶隔膜的三颈圆底烧瓶中。连续常压蒸馏直到达到一个恒定沸点（注解8）然后体积进一步减少到约40毫升。将产生的异构混合物过滤（注9），滤液用旋转蒸仪减压蒸馏浓缩以得到无色油状产品，凝固成半固体状白色物质。将该产品用100mL 异丙醚溶解并重结晶得到18.6-20.4克（50 - 55 %）特戊酰氯（注解10）。

2.2.注解注解注解

1. 所有试剂购自Aldrich 化学公司（除三甲基乙酰氯是论文审核者购自 Acros 公司），使用时没有进一步提纯，论文审核者用低温酒精温度计代替有特氟隆涂层的热电偶，烧瓶的第三个瓶颈与大气相通。

2.注射泵用于酰氯的添加以达到稳定流速，注射器针头尖端插入反应混合物液面下，在0～5℃滴加三甲基乙酰氯会导致立即形成沉淀。

3.在特戊酰氯添加结束时反应完成。对于5 L 或更大规模，反应在10 - 15°进行没有选择性的损失。

4. 这时候少量水合肼出现在在反应混合物中，但安全性评价表明最终反应混合物有非常低的热势。(DH=1

5.3 J/g)，这就造成真空蒸馏的最低热危险。

5．提交者用真空蒸馏收集反应混合物，(100 mm, bath temperature 70 °C, vapor temperature 51 °C)蒸馏收集后重约120g.审核者成功在65～70℃水浴下使用旋转蒸发进行实验，并采用一个防爆盾作为预防措施。

6.双酰化副产品（Me 3CCONHNHCOCMe 3）被过滤除去，用20mL 水洗涤滤饼。

7.提交者通过真空蒸馏除去溶剂(100 mm,bath temperature 70 °C, vapor

temperature 51 °C)

8.当蒸汽温度达到111 °C 时共沸除水完成

9. 氯化钠经过滤除去。

10. 提交者在没有重结晶的情况下获得72％的产率，用高效液相色谱（按面积;条件：250毫米Kromasil C4色谱柱采用乙腈（A ）/水（B ）和0.1％三氟乙酸水溶液（C ）,0:90:10的A:B:C 到90:0:10的A:B:C 过柱15分钟，并保持5分钟）确定产品为>97%纯。

废物处置信息

危险材料处理和处置应按照“实验室谨慎操作”；国家科学院出版社出版，华盛顿特区，1995年。

3.3.讨论讨论讨论

在杂环分子的合成中酰肼（RCONHNH 2）是非常有用的起始原料和中间体，酰肼可以用肼解酰胺，酯和硫酯合成，肼与酰氯或酸酐的反应也是众所周知的，但它因同时生成1,2-二乙酰基肼而显得复杂，往往要求使用无水肼从而出现很高的热危险。二酰基产品占主导地位时，肼与低分子量的脂肪酰氯反应，这使得反应没有实际生产意义。

最近，我们需要准备大量的特戊酰肼（1）查阅文献得以下几种方法（1）加热路易斯酸催化剂如活性氧化铝或二氧化钛及水合肼和特戊酸混合物（2）在高温（140°）加热水合肼与特戊酸乙酯（3）冷凝邻苯二甲酰肼与特戊酰氯然后邻苯二甲酰基团脱保护。（4）含硫三甲基乙酸乙酯与水合肼的反应。反应安全性评价表明，在差示扫描量热（DSC）实验中肼水合物起始温度约125°，并具有很高的热势(?H = 2500 J/g)这促使我们开发一种不需要加热的用于合成1的方法。经过一些实验我们确定特戊酰氯与肼的反应在水中有效的得到高产率，1和Me3CCONHNHCOCMe3是4:1的比例（2）。使用有机溶剂（甲醇，四氢呋喃，异丙醇）水必然导致形成两相混合物并主要形成2，反应以水为溶剂得到简化，在部分浓度二酰基酰肼副产2从反应混合物沉淀出来并可方便地通过过滤除去。用甲苯置换去除剩余的水并产生氯化钠沉淀，这沉淀也很容易通过过滤去除，然后滤液进一步浓缩得到1且有>97%的纯度，通常有55-75％的产率。这个合成步骤已轻松用于10kg批量的1的合成。