Aldehydes occupy an important place within the landscape of fine chemicals, notably due to their extensive use in a wide variety of products such as detergents, fragrances, insecticides, etc. The most straightforward type of reactions to produce aldehydes in an atom-efficient manner and direct way lies in the carboformylation of unsaturated compound. Among them, hydroformylation is the most developed of these transformations and the intense research activities led by academics and the industry in this field captures the importance of this process. However, this reaction does not only involves the use of toxic and flammable CO gas but has also a limited span in terms of chemical diversity as, beside the introduction of an aldehyde, solely a single C-H bond is created. In this regard, introducing simultaneously an aldehyde group and a substituent on the reacting unsaturated group would considerably increase the synthetic potential of the reaction in forming highly functionalized aldehyde intermediates. So far, only one example of such reaction in which a C-C bond is created alongside with the formation of an aldehyde had been reported by Grigg (only two publications). Although the seminal work demonstrated the possibility of such approach, very strict conditions on the structure of the reagents were necessary to produce the desired aldehyde.
In this view, Morandi and coworkers recently published in Nature a novel approach for the direct and selective carboformylation of alkynes using an aroyl chloride acting both as a source of CO and as electrophile carbon (DOI: 10.1038/s41557-020-00621-x). This method not only circumvents the use of toxic CO gas but also enables the formation of highly functionalized α,β-unsaturated aldehydes, otherwise made via very tedious synthetic methods. By applying an ingenious sequence of well-defined catalytic steps, the previously elusive carboformylation was finally achieved, providing the desired aldehyde products in high yield and high selectivity. An important point in the methodology involves the deconstruction of the aroyl chloride into a CO molecule and an aryl group, both subsequently coordinating the palladium catalyst. Next, the coordination of the alkyne is followed by the insertion of the aryl group and the CO onto the alkyne to form an acyl palladium complex which can be trapped by a hydrosilane to release the product of the reaction. Applying the new method to the synthesis of a wide range of highly functionalized aldehyde products could highlight the high applicability of the method.
The authors started their investigation by screening a large library of phosphines ligands in the palladium catalyzed reaction of ortho-tolyl acyl chloride with an internal alkyne in the presence of a hydrosilane. As minor amounts of the desired substituted aldehyde were observed, various commercial hydrosilanes were tested in order to trap the palladium acyl intermediate, revealing that the use of a sterically hindered silane was essential to reach high yields. Also, two phosphine ligands, BISBI (2,2′bis(diphenylphosphinomethyl)- 1,1′-biphenyl) and TDMPP (tris(2,6-dimethoxyphenyl)phosphine) turned out to have a superior activity on the other tested phosphines. Interestingly, the activity of each phosphine, BISBI or TDMPP, varied with the steric hindrance of the acyl chloride used. Also, it is suggested that within the catalysts formed using BISBI or TDMPP as ligand, the phosphine group in BISBI or the methoxy group in TDMPP are actually hemi-labile which allow for the creation of a vacant site on the metal, therefore accessible for coordination of a CO ligand or the alkyne substrate. Further optimization of the relative amounts of reagents revealed that a twofold excess of the acid chloride and the silane leads to higher yields.
After fine-tuning of the reaction conditions, a large set of aroyl chlorides were tested, also producing the corresponding functionalized aldehydes with good yields and high selectivity (forming predominantly the Z-isomer). Interestingly, 5-20% of the E-isomer were obtained in case of less sterically hindered aroyl chlorides, suggesting that ortho-substituents on the aroyl chloride prevent from the E/Z isomerization. Among all the tested aroyl chlorides, it is to be noted that the method allows for the introduction of interesting functionalities such as sulfonamides, aryl halogenides and even aryl boronates. However, when electron withdrawing substituted chlorides were used, a decrease in the yield and regioselectivity was observed, probably due to a less favored CO reinsertion, according to the authors. Experiments were successfully conducted on 25g scale, proving the applicability of the unprecedented method for the synthesis of highly functionalized aldehydes.
In a second phase of investigation of the reaction’s scope, a wide structural range of symmetrical and unsymmetrical internal alkynes were tested, using ortho-, para-toluoyl and mesitoyl chlorides. In the case of unsymmetrical alkynes, both the E- and Z- regioisomers are obtained but the regioselectivity appeared to be high enough to enable the easy separation of the α- and β-products (even in the case of several tethered ester-functionalized alkynes and a terbutyl substituted alkyne). Although small deviations were observed within the tested substrates, the regioselectivity of the reaction seems dominated by electronic effects induced by the substituents of the alkyne rather than steric effects. Unfortunately, the use of terminal alkynes could not afford the desired product due to possible polyinsertion side reactions. However, by reacting silyl-aryl alkynes and performing the deprotection afterward, the corresponding terminal aldehydes could be also obtained (although in a less straightforward manner).
Importantly, the authors demonstrate the very versatile character of the strategy by applying the concept for the development of new direct carbonylation methods (see scheme above). For instance, the use of stannane reagents instead of silanes results in the CO-free carboacylation of internal alkynes. Also, as the Pd-intermediate obtained by using an aliphatic acylchloride can undergo β-elimination to provide an alkene, both hydroformylation and hydroacylation can also be reached with this method, depending on the nucleophile involved (respectively a silane or a stannane reagent), and this without use of syngas.
This paper provides a very elegant and safe method for the unprecedented intermolecular carboformylation reaction of internal alkynes to form highly functionalized aldehydes, and this, without using toxic and flammable CO gas. Interestingly, the authors mention in the supporting information that thirty-five bisphosphine ligands and twenty-nine monophosphines were evaluated in this preliminary studies. This extended use of libraries of ligands highlights the essential role of high-throughput screening of catalysts, of ligands and conditions in the discovery of new reactivity. We hope that this work will encourage other groups in their efforts for the development of novel synthetic routes.
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Article: “Palladium-catalysed carboformylation of alkynes using acid chlorides as a dual carbon monoxide and carbon source”
By: Yong Ho Lee, Elliott H. Denton and Bill Morandi
Nat. Chem. 13, 123–130 (2021)