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.
1. Synthesis of Ynone
2. Aqueous Workup
3. Purification of Ynone
4. Characterization of Ynone
Initial efforts were focused around the preparation of ynone 1a from phenylacetylene trifluoroborate S1 and benzoyl chloride (Figure 1). Table 1 illustrates the optimization steps performed including screening of various Lewis acids, solvents, as well as examination of the effect of water on the reaction. Next, the scope of the reaction has been explored by submitting phenylacetylene trifluoroborate to the optimized conditions in the presence of a variety of acyl chlorides (Figure 2). Modest to excellent yields may be obtained depending on the nature of the acyl chloride substrate. The scope of the reaction has further been evaluated through the preparation of several additional examples of alkynyltrifluoroborate salts. Figure 3 illustrates selected examples of other alkynyltrifluoroborate salts that can be employed in the preparation of ynones under the developed conditions. Derivatives of phenylacetylene trifluoroborate bearing electron donating substituents afforded the corresponding ynone products in good to excellent yields while aliphatic derivatives of alkynyltrifluoroborate salts proved to be slightly less reactive affording modest yields.
Figure 1: Preparation of Ynone 1a from phenylacetylene trifluoroborate S1 and benzoyl chloride. Scheme illustrating the conditions for the preparation of ynone 1a including formation of the reactive dichloroborane intermediate.
Figure 2: Representative 1H NMR spectrum of ynone 1a. Chemical shifts and relative integrations of characteristic protons are labeled.
Figure 3: Representative 13C NMR spectrum of ynone 1a. Chemical shifts of characteristic carbons are labeled.
Figure 4: Representative HRMS spectrum of ynone 1a obtained via atmospheric-pressure chemical ionization. The measured m/z value of the [M+H]+ ion is reported.
Figure 5: Reactions of phenylacetylenetrifluoroborate salt S1 with acyl chlorides. Structures and yields for products produced by varying the identity of the acyl chloride starting material are illustrated. Reactions were run with 1 equiv of acyl chloride, 1.5 equiv potassium phenylacetylenetrifluoroborate S1, and 1.5 equiv boron trichloride.
Figure 6: Reactions of various alkynyltrifluoroborates with acyl chlorides. Structures and yields for products produced by varying the identity of the alkynyltrifluoroborate starting material are illustrated. Reactions were run with 1 equiv of acyl chloride, 2.5 equiv potassium organotrifluoroborate salt and 2.5 equiv boron trichloride.
Entry | Lewis acid | Lewis acid (equiv) | Conditions | Yield (%) |
1b | SiO2 | 16.5 | CH2Cl2 | 0 |
2 | SiCl4 | 1 | CH2Cl2 | trace |
3 | BF3·OEt2 | 1 | CH2Cl2 | trace |
4b | FeCl3 | 1 | CH2Cl2 | 24 |
5c | AlCl3 | 1 | CH2Cl2 | 62 |
6d | AlCl3 | 1 | CH2Cl2 | 66 |
7e | AlCl3 | 1 | CH2Cl2 | 60 |
8 | AlCl3 | 1 | THF | trace |
9 | AlCl3 | 1 | toluene | trace |
10 | AlCl3 | 2 | ClCH2CH2Cl | 33 |
11 | AlCl3 | 1 | DMSO | trace |
12 | AlCl3 | 2 | acetonitrile | trace |
13 | AlCl3·6H2O | 1 | CH2Cl2 | 0 |
14b | BCl3 | 1.5 | CH2Cl2 | 67 |
15 | BBr3 | 1 | CH2Cl2 | 20 |
Table 1: Optimization of conditions for the preparation of ynone 1aa. Yield of product 1a upon variation of reaction conditions and Lewis acid catalyst. aReactions were run with 1 equiv benzoyl chloride and 1 equiv potassium phenylacetylenetrifluoroborate S1. b1.5 equiv S1. cAnhydrous conditions. dThe reaction was done in non-dried glassware under air. eAnhydrous conditions + 1 µl of water.
Table 1 illustrates the steps taken to optimize the conditions for the reaction of phenylacetylene trifluoroborate with benzoyl chloride to form the corresponding ynone product. Initially, catalysts known to convert organotrifluoroborates to organodifluoroboranes were tested. Unfortunately Silica gel,35 silicon tetrachloride,36 and boron trifluoride31,32 did not promote the formation of the desired ynone (Table 1, entries 1-3). The use of chlorinated Lewis acid catalysts proved to be more successful. A low yield of the desired ynone 1a was obtained in the presence of an iron(III) chloride catalyst (Table 1, entry 4). Next, aluminum(III) chloride was investigated as a result of its well-established ability to promote oxocarbenium ion formation in Friedel-Crafts acylations.37-39 The desired product was obtained in 62% yield when an aluminum(III) chloride catalyst was employed.
Further optimization revealed that air and moisture have little effect on the yield of the reaction (Table 1, entries 5-7). As a result, subsequent reactions were performed in non-dried glassware in the presence of air. Attempts to optimize the solvent revealed that dichloromethane (DCM) is particularly well suited to the reaction (Table 1, entries 8-12). Inconsistencies in the results of reactions catalyzed by aluminum(III) chloride prompted the exploration of alternative catalysts. Commercially available aluminum(III) chloride hexahydrate was completely inactive under the reaction conditions (Table 1, entry 13). This is a good indicator that the formation of aluminum(III) chloride hydrate inhibits the reaction. Boron trichloride was found to produce similar yields with better consistency (Table 1, entry 14).
Upon interaction of the potassium alkynyltrifluoroborate with boron trichloride, a more reactive organodichloroborane species is formed.40 This initial step is critical for the reaction with the acyl chloride and formation of the ynone to proceed. Since organotrifluoroborate salts are not soluble in DCM, the reaction takes place as a heterogeneous mixture. After addition of boron trichloride, the solution is sonicated order to facilitate formation of the reactive dichloroborane species by increasing the surface area of the trifluoroborate salt available to react. Application of ultrasound waves to the reaction mixture causes mechanical effects through the generation of cavitation bubbles. During sonication, collapse of cavitation bubbles in the fluid results in localized areas of high temperatures and pressures.41 Shock waves are produced that create microscopic turbulence resulting in an increase in kinetic energy of the solid trifluoroborate salts. The increase in energy of the system during sonication promotes fragmentation of the trifluoroborate salt resulting increased surface area available to interact with boron trichloride. Sonication of the reaction mixture prior to addition of the acyl chloride starting material ensures the efficient formation of the reactive alkynyldichloroborane species without the need for more forcing conditions or longer reaction times.
Figure 2 illustrates the results obtained when phenylacetylene trifluoroborate was reacted with a variety of acyl chlorides under the optimized reaction conditions. Neutral aromatic (1b, 1c) and aliphatic (1j-l) acyl chlorides furnish the corresponding ynones in synthetically useful yields. Those acyl chlorides bearing electron donating groups (1d-g) provide excellent yields while electron withdrawing groups result in comparatively modest yields (1h, 1i, 1m). Interestingly, when the electron withdrawing group is located in the ortho position (1i, 59%), a significant yield increase is observed in comparison to the analogous para substituted acyl chloride (1h, 30%). The steric interaction of the substituent in the ortho- position may force the carbonyl functional group out of the plane, thereby offsetting the electron-withdrawing character of the aromatic ring. It is worth noting that 4-bromobutyryl chloride reacted to afford the desired product 1m in 39% yield. To our knowledge, this is the first protocol for the synthesis of ynones to tolerate an alkyl bromide functional group. Occasionally, when the acyl chloride starting material is neutral or electron deficient, aliphatic impurities appear on the proton NMR. This may necessitate a pentane wash in order to further purify the product. While possible, it is not economical to perform the pentane wash during the first purification stage since pentane is costly in comparison to hexanes. Completing the secondary purification separately on a smaller scale such as a Pasteur pipette column significantly reduces the amount of pentane required.
Figure 3 illustrates the effect of the identity of the alkynyltrifluoroborate salt on the yield of the reaction. In general, derivatives of the phenylacetylene trifluoroborate salt bearing electron-donating substituents on the aromatic ring reacted with aromatic and aliphatic acyl chlorides to produce the desired ynones in good to excellent yields (2a-c, 3a-c). Aliphatic alkynyltrifluoroborate salts proved to be less reactive substrates. Modest yields have been obtained when hexynyl- and cyclopentylethynyltrifluoroborate salts were reacted with electron-rich benzoyl chloride derivatives (4a, 5a).
In conclusion, a novel method for the preparation of ynones from acyl chlorides and potassium alkynyltrifluoroborate salts has been developed. The yields obtained for the synthesis of ynones by this method range from modest to excellent depending on the nature of the acyl chloride and trifluoroborate starting materials. In general those starting materials bearing electron donating substituents undergo the reaction more readily than starting materials bearing neutral and electron withdrawing functional groups. The value of this approach lies in the operational simplicity and functional group tolerance of the method. This straightforward, one-pot reaction proceeds rapidly at ambient temperature in the presence of boron trichloride without exclusion of air and moisture. This convenient method may be employed in the preparation of ynones in modest to excellent yields from a variety of acyl chlorides and alkynyltrifluoroborate salts.
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 |