The goal of this manuscript is to demonstrate a straightforward method for the preparation of ynones from acyl chloride and potassium alkynyltrifluoroborate salt starting materials. The one-pot reaction proceeds rapidly in the presence of boron trichloride without exclusion of air and moisture.
Ynones are a valuable functional group and building block in organic synthesis. Ynones serve as a precursor to many important organic functional groups and scaffolds. Traditional methods for the preparation of ynones are associated with drawbacks including harsh conditions, multiple purification steps, and the presence of unwanted byproducts. An alternative method for the straightforward preparation of ynones from acyl chlorides and potassium alkynyltrifluoroborate salts is described herein. The adoption of organotrifluoroborate salts as an alternative to organometallic reagents for the formation of new carbon-carbon bonds has a number of advantages. Potassium organotrifluoroborate salts are shelf stable, have good functional group tolerance, low toxicity, and a wide variety are straightforward to prepare. The title reaction proceeds rapidly at ambient temperature in the presence of a Lewis acid without the exclusion of air and moisture. Fair to excellent yields may be obtained via reaction of various aryl and alkyl acid chlorides with alkynyltrifluoroborate salts in the presence of boron trichloride.
The intention of this video is to demonstrate a straightforward approach for the preparation of compounds containing an ynone functional group from convenient starting materials. Ynones are valuable building blocks in organic chemistry that have been shown to have biomedical and material significance. Ynones are precursors to valuable organic functional groups including pyrimidines,1,2 quinolones,3 furans,4 pyrazoles,5,6 flavones,7 oximes,8 and chiral propargylic alcohols.9-11 A more convenient method for the preparation of ynones has been sought as a result of the drawbacks of traditional methods including poor functional group tolerance and tedious synthetic routes.
The reaction of metal12,13 and metalloid14 acetylides with acyl chlorides is one common route for the preparation of ynones. Alternatively, the synthesis of ynones from acyl chloride can be achieved via two-step procedures using Weinreb amides and organolithium or Grignard reagents.15 Another prevalent approach includes the addition of organolithium or Grignard reagents to an aldehyde, which is followed by the oxidation of a secondary alcohol to the corresponding ketone.16-19 Poor functional group tolerance of metal acetylides and the need to purify synthetic intermediates after each step are main deficiencies of the aforementioned methods. Transition-metal-catalyzed carbonylative couplings have recently emerged as an alternative approach for the preparation of ynones.20-22 Unfortunately, in addition to cost and toxicity associated with transition metals, metal-catalyzed carbonylative reactions often require elevated CO pressures and suffer from the presence of an undesired Sonogashira coupling byproduct. Given their utility in organic synthesis as well as the drawbacks associated with traditional synthetic methods, the development of a more straightforward method for the preparation of ynones is appealing.
Potassium organotrifluoroborate salts have recently emerged as versatile reagents in organic synthesis. Advantages including ease of preparation,23 inherent stability, low toxicity, and good functional group tolerance have made organotrifluoroborate salts attractive synthetic reagents.24-27 Organotrifluoroborate salts have been used primarily as a bench-stable equivalent of boronic acids for palladium-catalyzed Suzuki-Miyaura coupling.26 Recently, following a seminal work by Matteson and co-workers,28 Bode, Molander and others have highlighted the utility of organotrifluoroborates as reagents in non-metal catalyzed reactions.29-33 The field of transition-metal-free reactions of trifluoroborates is still in its infancy stage. Given the great potential for use of organotrifluoroborate salts in non-metal catalyzed organic synthesis, we sought to develop a novel method for the preparation of ynones from acyl chlorides and alkynyltrifluoroborate salts.
表1示出了采取优化条件为苯乙炔三氟与苯甲酰氯反应,形成相应的ynone产物的步骤。最初,公知的organotrifluoroborates转换为organodifluoroboranes催化剂进行了测试。不幸的是硅胶,35四氯化硅,36和三氟化硼31,32没有促进形成所需ynone的( 表1,条目1-3)。使用证明含氯路易斯酸催化剂,以获得更大的成功。在铁(III),氯化催化剂( 表1,条目4)的存在下获得所需的ynone 1a的低收率。接着,铝(III),氯化了研究,作为其既定的能力,以促进在弗里德尔-克拉夫茨酰化oxocarbenium离子形成的结果。37-39需要的产物,产率62%时获得的铝(III),氯化催化剂为EMPloyed。
进一步的优化显示,空气和水分对反应的收率( 表1,条目5-7)几乎没有影响。其结果是,随后的反应在非干燥的玻璃器皿中进行在空气的存在。尝试优化溶剂透露二氯甲烷(DCM)是特别适合的反应( 表1,条目8-12)。在反应铝(III)氯化物催化的结果不一致促使替代性催化剂的探索。市售的铝(III),氯化六水合物是在反应条件( 表1,条目13)下完全失活。这是一个很好的指标,铝(III),氯化水合物的形成抑制该反应。三氯化硼被发现产生类似的产量具有更好的一致性( 表1,条目14)。
当钾alkynyltriflu互动oroborate用三氯化硼,更活泼的organodichloroborane物种形成。40该初始步骤是用于与酰氯的ynone并形成进行该反应的关键。因为organotrifluoroborate盐不溶于DCM中,将反应发生的非均相混合物。另外三氯化硼后,将溶液超声处理顺序通过增加三氟盐的可用以使该表面积,以促进形成反应二氯硼物种。超声波在反应混合物中的应用程序将导致通过空化气泡的产生机械影响。期间超声处理,空化气泡塌陷在流体导致高的温度和压力的局部区域41中冲击波产生的创建导致增加在固体三氟盐的动能微观湍流。期间超声促销系统中的能量的增加对三氟盐TES碎片而增加的表面积与三氯化硼交互。将反应混合物之前加入酰基氯为起始材料的超声处理保证了有效形成反应alkynyldichloroborane物种,而不需要更多的强制条件或更长的反应时间。
图2示出了当苯乙炔三氟用优化的反应条件下的各种酰氯的反应,所得到的结果。中性芳族(1B,1C)和脂族(1J-1)酰氯提供相应ynones在合成有用的产率。这些酰氯带有电子基团(1D-G)提供了良好的收益,而吸电子基团导致相对温和的收益率(1H,1I,1M)。有兴趣的朋友stingly,当吸电子基团位于邻位 (1I,59%),一显著产量增加相比于类似的对位观察取代的酰基氯(1H,30%)。该取代基中的邻位位置上的空间相互作用可能迫使羰基官能团出的平面,从而抵消了芳香环的吸电子性质。值得一提的是,4-溴丁酰氯反应,得到39%收率的所需产物1m上。据我们所知,这是第一个协议ynones合成容忍烷基溴官能团。偶尔,当酰基氯原料是中性或缺电子,脂族杂质出现在质子NMR。这可能需要一个戊烷洗涤以进一步提纯产物。虽然有可能,这是不经济的第一纯化S期期间执行戊烷洗因斯戊烷是昂贵相比己烷。二次纯化以较小规模分别完成诸如巴斯德吸管柱显著降低戊烷所需的量。
图3示出的alkynyltrifluoroborate盐的身份对反应产率的影响。在通常情况下,芳环上的苯基乙炔三氟盐轴承的给电子取代基的衍生物反应,用芳族和脂族酰基的氯化物,以产生所需的ynones良好至优良产率(2A-2C,3A-C)。脂族alkynyltrifluoroborate盐证明是较低反应性的底物。当hexynyl-和cyclopentylethynyltrifluoroborate盐进行反应与富电子苯甲酰氯衍生物(4α,5α)适度的产量已经被获得。
总之,新方法的编写Øf起酰基氯化物和钾alkynyltrifluoroborate盐ynones已经研制成功。通过该方法的范围从温和到优良取决于酰氯的性质获得ynones的合成收率和三氟起始原料。在一般的那些起始物承载给电子取代基进行反应更容易地比起始材料轴承中性和吸电子官能团。这种方法的价值在于方法的操作简便性和官能团的耐受性。这种直接的,一锅反应在环境温度下在三氯化硼的存在下迅速进行,而不排斥空气和湿气的。这种简便的方法可以采用ynones的制剂谦虚良好的收益从各种酰氯和alkynyltrifluoroborate盐。
The authors have nothing to disclose.
This work was supported by the UOIT start-up fund. We thank Mr. Matthew Baxter (UOIT) for his assistance in the laboratory.
Name of Material/ Equipment | Company | Catalog Number | Comments/Description |
Sonicator | VGT | 1860QT | Ultrasonic cleaner. Similar sonication devices may be used. |
Dichloromethane | Sigma | 270997 | Anhydrous |
Boron trichloride solution | Sigma | 178934 | 1M solution in DCM |
Acyl chloride | Sigma | Various | Acyl chlorides from other suppliers such as Alfa Aesar may be used. Caution – refer to MSDS for safety information. |
Potassium alkynyltrifluoroborate salt | N/A | N/A | Synthesized23 from terminal alkyne |
Ethyl acetate | ACP | E-2000 | ACS grade |
Hexanes | ACP | H-3500 | ACS grade |
Pentane | Sigma | 236705 | Anhydrous |
Magnesium sulfate | Sigma | M7506 | |
Filter paper | Whatman | 1093 126 | Student grade. This speceific variety is not necessary. |
Silica Gel 60 | EMD | 1.11567.9026 | Particle size 0.040-0.063 |